Attenuation of emotional and nonemotional memories after their reactivation: role of beta adrenergic receptors.

A memory trace in its active state is susceptible to interference by amnesic agents, such as hypothermia and electroconvulsive shock, and by NMDA receptor antagonists, suggesting that a time-dependent consolidation process occurs each time a memory is reactivated. The role of beta noradrenergic receptors in reconsolidation in rats was examined in both a positively reinforced radial maze task and a footshock-reinforced conditioned emotional response task. For the former, rats were trained over several days in a spatial reference memory task and received a single reactivation trial followed by propranolol. A temporally graded impairment was observed when propranolol treatment occurred after the memory reactivation trial. In the emotional task, memory impairing effects of propranolol were greater when the drug was administered after a reactivation trial than when administered immediately after the initial training. These results suggest that reactivation of memory triggers a beta receptor-dependent cascade of intracellular events, recapitulating that which occurs during initial postacquisition consolidation, thus permitting reorganization of the existing memory as a function of new information in the retrieval environment. This remarkable lability of an active memory trace provides a new basis for pharmacotherapeutic intervention in such syndromes as Posttraumatic Stress Disorder. beta adrenoreceptor antagonists may be promising pharmacological agents for attenuating debilitating memories at the time of their controlled reactivation.

Consolidation of memory for odor-reward association: beta-adrenergic receptor involvement in the late phase.

Experimentally naive rats can learn rapidly to discriminate among three odors to obtain food reinforcement. After three massed trials, they show almost errorless performance. This task has proved to be useful in studying time-dependent postacquisition intracellular processes necessary for long-term memory. The present experiments evaluated the temporal dynamics of the role of beta-noradrenergic receptors in long-term consolidation. Rats were implanted with intracerebroventricular cannulae and trained in a single session to find reinforcement in a hole in a sponge impregnated with a particular odor. Injections of the beta-receptor antagonist timolol were made at 5 min, 1, 2, or 5 hr after training. Memory and relearning ability were evaluated 48 hr later. Rats treated with timolol 2 hr after training showed a memory deficit at the retention test, but were able to relearn the task normally. Injections at the earlier or later time points were ineffective. The results reinforce previous observations with systemic injections that beta-noradrenergic receptors are involved in the late phase of memory consolidation and suggest a critical time window during which they are necessary. The time window is compatible with the current view that long-term memory depends on late involvement of the cAMP cascade leading to new protein synthesis necessary for synaptic reorganization.

Reconsolidation of memory after its reactivation.

We report here data suggesting that reactivation of a well-established memory by a retention test triggers cellular events which depend upon N-methyl-D-aspartate (NMDA) receptors for up to 2 h after reactivation. Rats were overtrained on a maze task requiring integration of distal spatial information contained in cues strategically placed around the maze. Previous experiments showed that pretrial injection of the noncompetitive NMDA receptor antagonist, MK-801, at a dose which had no effect on overt behavior (0.05 mg/kg), markedly disrupted the well-trained performance of the task. Surprisingly, the behavioral deficit persisted on subsequent, drug-free trials, 24 h later. The present experiments showed that post-trial injections produced the same effects on performance on one or two subsequent daily trials. A temporal gradient for this amnestic effect of the drug treatment was established by injecting rats at 5, 30, 60, 90, 120 or 180 min after the performance trial. Only those rats whose MK-801 treatment was delayed for 120 min or more after the trial were able to perform the task normally 24 h later. All other treatment times induced significant amnesia for the task, when the rats were tested 24 h later. A subsequent experiment, using a more difficult version of the task, showed a longer amnesia gradient, but the predrug performance level could be reinstated within one multiple trial test session. Thus, it appears that activation of a well-established memory circuit renders the trace labile, requiring its reconsolidation. To what extent the entire post-acquisition cascade of NMDA receptor-dependent intracellular events is recapitulated each time a memory is activated and reorganised is probably a function of the age and complexity of the memory and the amount of new information to be integrated into the circuit. These results provide physiological evidence for the notion that memory is a dynamic process undergoing continual reorganization as a function of the ongoing experience of the organism.

Antibody to day-old chick brain glycoprotein produces amnesia in adult rats.

Polyclonal antibody R-1, raised against a chick synaptic membrane glycoprotein fraction whose synthesis is enhanced following training on a passive avoidance task, produces amnesia when injected into chick forebrain 5.5 h posttraining. The amnestic IgG fraction specifically recognizes a low sialylated isoform of NCAM (Mileusnic Rose, Lancashire, & Bullock, 1995). We have now investigated the effects of this antibody on memory formation in adult rats. R-1, preimmune serum, or saline was injected intracerebroventricularly 5.5 h posttraining through bilaterally implanted cannulae. Rats injected with R-1 and tested 48 h later showed a significant amnesia for avoidance compared with the controls. Amnesia was not apparent at 24 h posttraining. R-1 injections were without effect on spontaneous locomotor or exploratory activity in a holeboard test. The results contribute to the argument that the role of cell adhesion molecules in neuronal plasticity is not limited to the developing nervous system, but they play a more general role in the experience-dependent synaptic remodeling underlying long-term memory.

Experience-dependent maturation of the spatial and temporal characteristics of the cell receptive fields in the kitten visual cortex.

The development of contrast sensitivity to spatial and temporal frequencies was studied in the visual cortex of 6-week-old kittens reared from birth in three conditions: normal, dark-reared (DR) and dark-reared after 6 h of visual experience. Receptive fields of cells recorded in area 17 were quantitatively analysed using drifting sine-wave gratings. Compared to the low values obtained in the DR kittens, we observed after 6 h of visual experience: (1) an adult-like detection of higher spatial frequencies, (2) an increase of contrast sensitivity at low temporal frequencies; (3) a shift of the cell optimum towards 3 Hz, all values close to the normal ones. Unlike the spatial frequency selectivity, contrast sensitivity and detection of higher temporal frequencies continue to develop with age and visual experience.

Temporal correlations in modulated evoked responses in the visual cortical cells of the cat.

We analysed evoked responses recorded from 97 cells in the visual cortex of 4 adult cats and 8 kittens, stimulated by a drifting sinusoidal grating. A Fourier analysis of the responses allowed us to select 30 cells showing a clear modulating response (relative modulation index greater than 1). The 162 records from these selected cells were scanned to detect precise temporal correlations in the form of replicating triplets and associated "ghost" doublets. Temporal correlations of this nature were observed in these cells. They are about 10 times more abundant in adult cats than in kittens, and mostly observed in infragranular cortical layer cells. The possible role of these precise temporal patterns in information processing in the brain is examined, as well as the relation between this type of temporal correlation with coherent oscillations and principal components waveforms.

Visual field in dark-reared cats after an extended period of recovery.

The visual field of dark-reared cats was behaviourally measured after several years of recovery in a normal environment. A reduction of the visual field was observed and affected the contralateral field as well as the ipsilateral field when tested in monocular viewing. The longer the deprivation period, the more reduced was the visual field. Our results suggest that binocular deprivation might have stabilized the visual system in an immature state.

[Temporal correlations and coding of information in the visual cortex of the cat]. / Corrélations temporelles et codage de l'information dans le cortex visuel du chat.

We have observed repeated patterns in evoked spike trains recorded from the primary visual cortex of the cat. These patterns are called "triplets" and "ghost doublets". Triplets are groups of three pulses, that may or may not be adjacent to one other, the mutual intervals of which are replicated in one other group of three spikes with a precision higher than 0.15 ms. Ghost doublets are doublets of pulses whose interval replicates, with the above precision, one of the intervals of the repeated triplets and are also present in the record. In one of the 9 recorded cells, in which pulses were clearly emitted in bursts in phase with the drifting of the sinusoidal grating used as a stimulus, we could show that local temporal correlations in the form of replicating triplets and ghost doublets correspond very precisely to the temporal phase of the grating: the study of the distance between triplets, or between triplets and ghost doublets, gives a remarkably precise value of the time frequency of the grating.

Visual localization and discrimination after ibotenic lesion of the cat orbito-insular cortex.

Behavioral tasks were used to investigate how the orbito-insular cortex (OIC) of the cat is involved in complex operations such as the orienting reaction towards a novel stimulus. Six cats were trained preoperatively on a perimetry test to assess their ability to orient the head and eyes to objects presented in restricted regions of the visual field, and on brightness, pattern and form discrimination tasks for food reward in a two-choice discrimination apparatus. Two animals then underwent unilateral chemical lesion of the OIC using injections of ibotenic acid, two others received bilateral lesions of this same area, and the remaining two cats were used as normal controls. Postoperative performance of brightness, pattern and form discrimination was normal following OIC lesions, and no lack of retention was observed. In contrast, the cats with OIC lesions had significant deficits in their visually guided behavior. The cats ignored objects presented in the monocular segment of both sides of the visual field, even after unilateral lesion, and there was an effect on the ability to attend and fixate the central preconditioned stimulus.

An anatomical investigation of visual inputs to the cat orbital cortex.

The orbital region of the cortex in the cat is known to be involved in multimodal sensory functions. Visual afferent connections of this area have been investigated using the horseradish peroxidase technique. Our results demonstrate the existence of projections from ipsilateral thalamic nuclei essentially at the suprageniculate and magnocellular medial geniculate junction, well known to have multimodal physiological properties.

[Passive electrical constants of skeletal muscular fibres studied in different muscles of normal and thiamine deficient rats (author's transl)]. / Constantes électriques passives des fibres musculaires squelettiques du rat: etude sur divers muscles normaux et carencés en thiamine

10 Some effects of thiamine deficiency were studied in three skeletal rat muscles, having different proportions of "fast" and "slow" fibres: extensor longus digiti IV (a nearly pure fast muscle), soleus (having a predominant population of slow fibres) and diaphragm muscle (mixed fibre population). 20 Cross section area of fibres (fig. 2) is reduced in thiamine deficient animals, mostly for fast fibres having a glycolytic metabolism, the histochemical profile of which tends to become similar to that of slow fibres, in which oxydative metabolism is predominant, as shown by a marked increase in succinodehydrogenase activity. 30 Measurements of resting potential E, of membranes time constant tau and of fibre input resistance R were performed in normal and thiamine deficient muscles (table I). R and tau were obtained from square pulse analysis, using a double shifted sampling method permitting the use of a single microelectrode. E is not greatly affected by thiamine deficiency. tau changes appear not to be significant, except for fast fibres from extensor longus muscle, where tau is slightly reduced. R is increased in thiamine deficient animals (fig. 3). 40 Changes in R and tau do not exactly follow the predictions of cable theory, if one assumes that a purely dimensional factor is involved. Thus, the view that thiamine deficiency does not change basic passive electrical constants of fibres (membrane specific resistance and capacity, myoplasm resistivity) can be considered only as a first approximation. 50 R and tau values obtained in normal muscles are larger than data taken from other studies. The reasons for this discrepancy are discussed. It is suggested that diet differences may play a role.