Faculty Bibliography

A polyclonal antibody (R1), raised against chick synaptic membrane glycoproteins and recognizing the neural cell adhesion molecule (NCAM) caused amnesia for avoidance tasks when injected into day-old chicks and adult rats 5.5 h post-training. We investigated the effects of R1 antibody on memory formation in a non-aversive task, where stress is minimal: a massed trial odour discrimination task in rats. Preimmune serum or R1 antibody was injected i.c.v. 5.5 h after the last training session. Forty-eight hours after the training session, control rats showed very good retention whereas R1 antibody injection significantly disrupted retention. The results suggest that glycoproteins recognized by R1 in the rat play a specific role in memory formation for appetitive events as well as in memory formation for aversive situations

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

In order to relate noradrenaline-dependent potentiation in the dentate gyrus to behavioural events, rats were made to explore an environment in which their encounters with novel stimuli could be strictly controlled and monitored. Previous experiments have shown that an encounter with novel objects in a holeboard elicits a burst response in a large population of noradrenergic neurons of the locus coeruleus. Such a burst response has been demonstrated to produce a large and transient potentiation of the population spike in the dentate gyrus. In the present series of experiments, rats were chronically implanted with stimulating electrodes in the perforant pathway and recording electrodes in the dentate gyrus. Evoked potentials were monitored in the awake rat, first while it was resting quietly in a familiar environment and then while it was exploring the holeboard containing a novel object in a specific hole. There was a tonic increase in population spike amplitude when the rat was placed in the novel holeboard environment, but this effect gradually dissipated. This increase was partly blocked by the beta-noradrenergic antagonist propranolol. In addition there was a robust phasic increase in spike amplitude when the rat encountered a novel stimulus. This phasic response lasted approximately 50-75 s and was absent in animals treated with propranolol. These results show that a behavioural encounter with a novel stimulus can transiently enhance information transmission through the hippocampus, and suggest that activation of the noradrenergic system by the novel stimulus mediates this behavior-dependent gating

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

The auditory response of locus coeruleus (LC) neurones evoked by novel tones was investigated in anaesthetized and awake rats. Recording the single unit activity of LC neurones, responses to auditory stimuli are found under anaesthesia as well as in the awake animal. There are three types of LC responses to tone: first and by far the most frequent, a burst of several spikes at onset of the tone; second, a burst at tone offset and lastly, a total inhibition to the tone. All responses present a rapid habituation after the first few presentations of the stimulus. The results support the view that the LC plays a role in mediating responses to environmental changes

These experiments were designed to investigate the role of the noradrenergic system in promoting investigation of novelty in rats. Behavior was monitored in a hole board equipped with photoelectric cells strategically placed so that locomotor activity, rearing and investigation of each of the holes could be quantified independently. Specially designed computer software permitted recording of the sequence and cumulative duration of the visits to specific holes throughout the session. Dose-response curves of the sedative effect of the alpha 2 adrenergic receptor agonist clonidine were established, a sedative effect being defined as a decrease in overall horizontal displacements, rearings and hole visits. After a one week interval, the rats were rerun in the holeboard, with novel objects placed in four of the nine holes. Previous experiments had shown that rats spend significantly more time investigating holes containing objects than empty holes in this apparatus and this was replicated here. Doses of clonidine which were below threshold for inducing any sedative effect (10 micrograms/kg) totally eliminated preference for holes with objects while having no effect on total time investigating the holes. A subsequent experiment showed that the beta receptor antagonist propranolol (10 mg/kg) produced a similar effect. These results suggest that the noradrenergic system is implicated in stimulus seeking behavior and the post-synaptic beta receptors are involved in mediating the behavior

The functional influence of the frontal cortex (FC) on the noradrenergic nucleus locus coeruleus (LC) was studied in the rat under ketamine anesthesia. The FC was inactivated by local infusion of lidocaine or ice-cold Ringer's solution while recording neuronal activity simultaneously in FC and LC. Lidocaine produced a transient increase in activity in FC, accompanied by a decrease in LC unit and multiunit activity. This was followed by a total inactivation of FC and a sustained increase in firing rate of LC neurons. Subsequent experiments revealed antidromic responses in the FC when stimulation was applied to the LC region. The antidromic responses in FC were found in a population of neurons (about 8%) restricted to the dorsomedial area, FR2. The results indicate that there is a strong inhibitory influence of FC on the tonic activity of LC neurons. The antidromic responses in FC to stimulation of the LC region suggest that this influence is locally mediated, perhaps through interneurons within the nucleus or neighboring the LC

Activity of single units of the noradrenergic nucleus locus coeruleus was recorded in rats during active exploration of a novel environment. Novelty was controlled by the placement of objects in given holes in a hole board. The basic protocol included a habituation session in which the holes were empty and an object session in which a novel object was placed in one of the two holes. During the habituation session, when the whole environment was unfamiliar, there was a phasic response the first time the rat visited any hole, which habituated after one visit. During the second session, when one of the holes contained an object, the cell fired when the rat encountered the novel object. There was no response to empty holes in this session. The neuronal response was markedly diminished or entirely absent on the second and subsequent visits to object-containing holes, indicative of rapid habituation. In some rats it was possible to run a second object session, when a new object was introduced into a previously empty hole. Visits to this hole elicited a robust response, which again habituated after one single visit. The results show that the responses of locus coeruleus to novelty or change, which has been demonstrated in formal learning situations, occurs in freely behaving rats while they are learning about a new environment. Moreover, the response to novelty and change in the environment is short-lived, rapidly habituating after one or two encounters with the stimulus

Maudsley reactive (MR) and Maudsley nonreactive (MNRA) rats were submitted to a single session of acute 5-min immobilization stress and immediately sacrificed by decapitation. Subsequent neurochemical analysis revealed an elevation of 3,4-dihydroxyphenylacetic acid levels in the locus coeruleus and in the ventrolateral medulla, but not in the dorsomedial medulla, of rats of the two strains compared with nonstressed controls. This response was greater in the MR than in the MNRA group, suggesting a strain difference in the reactivity of the central noradrenergic cells to acute stress

Previous studies have shown that, in addition to partial damage to the cholinergic system, partial fornix section causes changes in the noradrenergic (NA) system and an increase in NA activity in the dorsal hippocampus. Behaviorally, this NA hyperactivity contributes to the deficits observed in the radial arm maze, since a reduction of NA activity restores the performance of rats with a partial fornix lesion. The reorganization of the NA system after partial fornix section should modify its responsiveness, and the present series of experiments examines these changes. In the first experiment, sensitivity to the sedative effects of the alpha 2 agonist clonidine was evaluated by determining a dose-response curve to clonidine in a hole board. Rats with partial fornix lesion were resistant to the sedative effects of clonidine, suggesting differences in alpha 2-receptor sensitivity. In the second experiments, rats were submitted to a test for novelty-seeking behavior in the hole board with objects placed in some holes. Rats with fornix sections spent more time in contact with novel objects than the control rats, a behavior which has previously been observed in hyper-noradrenergic animals. Finally, single-unit recording of locus coeruleus (LC) cells in anesthetized rats showed there were no effects of the partial fornix lesion either on spontaneous firing rate of LC cells or on their responsiveness to clonidine. These last results suggest that the behavioral differences and differences in NA activity observed after partial denervation are a result of local regulation of release at the NA terminals and are not due to changes in the cell bodies within the LC