Faculty Bibliography

Piriform cortex (PCx) is the primary cortical projection region for olfactory information and has bidirectional monosynaptic connections with olfactory bulb and association cortices. PCx neurons display a complex receptive field, responding to odours rather than their molecular components, suggesting that these neurons are involved in higher order olfactory processing. Neuromodulators, especially noradrenaline (NA), have important influences on sensory processing in other cortical regions and might be responsible for the plasticity observed in PCx during learning. The present study is the first attempt to examine in vivo the actions of NA on sensory responses in the PCx. Stimulation of the noradrenergic nucleus locus coeruleus (LC) was used to induce release of NA in the forebrain in urethane-anaesthetized rats. Extracellular recording of single units was made simultaneously in anterior and posterior PCx. The responses to an odour stimulus were measured over 25 trials. Twenty-five subsequent odour presentations were preceded by stimulation of the ipsilateral LC through a bipolar electrode, previously placed in the LC under electrophysiological control. This priming stimulation modified the activity of 77 of the 135 recorded neurons. For most cells, LC stimulation enhanced cortical responses to odour in terms of both spike count and temporal organization, with some differential effects in anterior and posterior regions. These results are the first to show enhancement of sensory responses in the olfactory cortex by LC activation. Spontaneous activation of LC neurons such as occurs during learning could serve to enhance olfactory perception and promote learning

Although there is growing knowledge about intracellular mechanisms underlying neuronal plasticity and memory consolidation and reconsolidation after retrieval, information concerning the interaction among brain areas during formation and retrieval of memory is relatively sparse and fragmented. Addressing this question requires simultaneous monitoring of activity in multiple brain regions during learning, the post-acquisition consolidation period, and retrieval and subsequent reconsolidation. Immunoreaction to the immediate early gene c-fos is a powerful tool to mark neuronal activation of specific populations of neurons. Using this method, we are able to report, for the first time, post-training activation of a network of closely related brain regions, particularly in the frontal cortex and the basolateral amygdala (BLA), that is specific to the learning of an odor-reward association. On the other hand, retrieval of a well-established associative memory trace does not seem to differentially activate the same regions. The amygdala, in particular, is not engaged after retrieval, whereas the lateral habenula (LHab) shows strong activation that is restricted to animals having previously learned the association. Although intracellular mechanisms may be similar during consolidation and reconsolidation, this study indicates that different brain circuits are involved in the two processes, at least with respect to a rapidly learned olfactory task

To characterize the electrophysiological properties of neurons in the medial agranular frontal cortex (Fr2) with respect to arousal level and locus coeruleus (LC) activity, we recorded spontaneous and auditory-evoked single unit activity in these areas simultaneously during different states of arousal in the rat. In the low-arousal state, as determined by EEG, 14/56 Fr2 neurons showed a tonic increase in spontaneous firing rate and 9/56 presented a clear inhibitory response to tone (onset latency 37 ms, duration 200 ms). The inhibitory response was not clear during the high-arousal state. Cross-correlation analysis of pairs of Fr2 and LC units, excluding activity during the actual tone, also showed a negative correlation from 120 ms before, to 170 ms after, Fr2 discharge in 5/63 pairs, only during low arousal. Significantly, 4/5 of the Fr2 neurons having this negative correlation with LC were included in that population which showed a tonic increase in spontaneous firing rate and inhibited to tone during low arousal. LC neurons, on the other hand, all showed excitation to tone stimulation (peak latency 30 ms), and response amplitude was not affected by changes in arousal level. The negative correlation in spontaneous activity, as well as their differential responses to tone, suggests an interaction between a select population of Fr2 neurons and the LC during the low-arousal state. Future studies with lesion or pharmacological manipulations would be necessary to confirm the presence of this interaction

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

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

Changes in binding of [3H]dizocilpine maleate to N-methyl-D-aspartate-sensitive ion channel receptors were evaluated after learning in order to specify brain regions which might be involved in memory formation. Rats were trained in a five-trial session of 40 min, to discriminate among three odours to obtain food reinforcement. Another group was trained in an eight-arm maze to choose always the same three arms to obtain food reinforcement (nine trials over 150 min). In rats killed 30 min after odour discrimination learning, dizocilpine maleate binding was significantly reduced in hippocampal sub-regions CA3, CA1 and fascia dentata and in frontal cortex. After spatial learning, changes in binding were limited to the amygdala, where a decrease was also observed. These results indicate that functional changes occur in specific brain regions after learning and suggest anatomical loci for further study of synaptic changes at a morphological level, after spatial learning or odour discrimination

The importance of the behavioural situation, attentional demands of the task, and stimulus-reinforcement contingencies in promoting or permitting experience-dependent neuronal plasticity is argued. Evidence is provided for the specific activation of the locus coeruleus noradrenergic system of the rat by novel stimuli encountered while investigating the environment, as well as during a formal learning situation. Noradrenergic neurons are particularly concerned with changes in the predictive value of the stimulus, when new learning should occur. Noradrenaline, released at LC terminals in target sensory systems, could facilitate shifts in attention, information processing and memory through its well-documented gating and tuning effects and its permissive role in long-term potentiation. Dopamine neurons, which fire persistently to reward during learning, could be involved in maintaining the behavioural response

Multiunit or single unit activity recorded simultaneously from frontal cortex (FC) and locus coeruleus (LC) under ketamine anesthesia revealed that both regions show slow oscillatory activity, together or separately. If, however, both regions are engaged in this oscillatory activity, there is a systematic relationship between their phases with peak LC firing always following FC firing by 200-400 ms. This was confirmed by cross-correlational analyses, which indicated that the two structures temporarily form a resonant system. The FC-LC resonant state is, however, loose enough to remain open to other intrinsic or extrinsic influences, keeping the measured frequencies of oscillations at each site slightly different, as demonstrated by a detailed analysis of the autocorrelograms. An injection of lidocaine at the frontal cortex site, while sharply reducing the prefrontal activity to essentially zero, leads to an increase of the LC activity and to a modification of the shape of the LC autocorrelogram, but does not change appreciably the phase relationship between the activity in the two structures during the diminishing activity in FC