Faculty Bibliography

Non-rapid eye movement sleep has been strongly implicated in consolidation of both declarative and procedural memory in humans. Elevated sleep-spindle density in slow-wave sleep after learning has been shown recently in humans. It has been proposed that sleep spindles, 12-15 Hz oscillations superimposed on slow waves (<1 Hz), in concert with high-frequency hippocampal sharp waves/ripples, promote neural plasticity underlying remote memory formation. The present study reports the first indication of learning-associated increase in spindle density in the rat, providing an animal model to study the role of brain oscillations in memory consolidation during sleep. An odor-reward association task, analogous in many respects to human paired-associate learning, is rapidly learned and leads to robust memory in rats. Rats learned the task over 10 massed trials within a single session, and EEG was monitored for 3 h after learning. Learning-induced increase in spindle density is reliably reproduced in rats in two different learning situations, differing primarily in the behavioral component of the task. This increase in spindle density is also present after reactivation of remote memory and in situations when memory update is required; it is not observed after noncontingent exposure to reward and training context. The latter results substantially extend findings in humans. The magnitude of increase (approximately 25%) and the time window of maximal effect (approximately 1 h after sleep onset) were remarkably similar to human data, making this a valid rodent model to study network interactions through the use of simultaneous unit recordings and local field potentials during postlearning sleep

Slow oscillations originating in the prefrontal neocortex during slow-wave sleep (SWS) group neuronal network activity and thereby presumably support the consolidation of memories. Here, we investigated whether the grouping influence of slow oscillations extends to hippocampal sharp wave-ripple (SPW) activity thought to underlie memory replay processes during SWS. The prefrontal surface EEG and multiunit activity (MUA), along with hippocampal local field potentials (LFP) from CA1, were recorded in rats during sleep. Average spindle and ripple activity and event correlation histograms of SPWs were calculated, time-locked to half-waves of slow oscillations. Results confirm decreased prefrontal MUA and spindle activity during EEG slow oscillation negativity and increases in this activity during subsequent positivity. A remarkably close temporal link was revealed between slow oscillations and hippocampal activity, with ripple activity and SPWs being also distinctly decreased during negative half-waves and increased during slow oscillation positivity. Fine-grained analyses of temporal dynamics revealed for the slow oscillation a phase delay of approximately 90 ms with reference to up and down states of prefrontal MUA, and of only approximately 60 ms with reference to changes in SPWs, indicating that up and down states in prefrontal MUA precede corresponding changes in hippocampal SPWs by approximately 30 ms. Results support the notion that the depolarizing surface-positive phase of the slow oscillation and the associated up state of prefrontal excitation promotes hippocampal SPWs via efferent pathways. The preceding disfacilitation of hippocampal events temporally coupled to the negative slow oscillation half-wave appears to serve a synchronizing role in this neocorticohippocampal interplay

Unraveling the functional role of neuromodulatory systems has been a major challenge for cognitive neuroscience, giving rise to theories ranging from a simple role in vigilance to complex models concerning decision making, prediction errors or unexpected uncertainty. A new, simplified and overarching theory of noradrenaline function is inspired by an invertebrate model: neuromodulators in crustacea abruptly interrupt activity in neural networks and reorganize the elements into new functional networks determining the behavioral output. Analogously in mammals, phasic activation of noradrenergic neurons of the locus coeruleus in time with cognitive shifts could provoke or facilitate dynamic reorganization of target neural networks, permitting rapid behavioral adaptation to changing environmental imperatives. Detailed analysis and discussion of extensive electrophysiological data from the locus coeruleus of rats and monkeys in controlled behavioral situations is provided here to support this view. This simplified 'new look' at locus coeruleus noradrenaline function redirects the challenge of understanding neuromodulatory systems towards their target networks, particularly to the dynamics of their interactions and how they organize adaptive behavior

A rapidly learned odor discrimination task based on spontaneous foraging behavior of the rat was used to evaluate the role of N-methyl-D-aspartate (NMDA) receptors (NMDARs) in ongoing memory consolidation. Rats were trained in a single session to discriminate among three odors, one of which was associated with palatable food reward. Previous experiments showed that the NMDAR antagonist DL-APV induced amnesia for this task when injected immediately after training. In the present study, memory was reactivated 24 h after training by exposure to the rewarded odor within the experimental context after which rats received an intracerebroventricular injection of APV. Combined reactivation-drug treatment induced profound amnesia when tested 48 h later. Animals receiving drug alone, in absence of reactivation, showed perfect retention. It is concluded that NMDARs support a consolidation process taking place after memory reactivation

Regulation of attention and promotion of behavioural flexibility are functions attributed to both the noradrenergic nucleus locus coeruleus (LC) and the prefrontal cortex (PFC). The PFC receives a large innervation from LC and small changes in catecholaminergic activity in PFC profoundly affect cognitive function. It is crucial to the understanding of learning-related plasticity, that the cognitive context driving LC neurons be determined and the relation to activity in PFC be elucidated. To this end simultaneous recordings were made from LC and prelimbic cortex (PL) during an odour-reward association task in the rat. Neuronal activity related to orientation of attention, reward predictability, reward itself, and changes in stimulus reinforcement contingencies, was measured. All LC neurons and a significant proportion of PL neurons were engaged during several aspects of a Go/NoGo task, especially after the signal for trial onset and CS+ presentation. LC activation was, however, more tightly aligned to the behavioural response than to the CS+ 22% of PL neurons were activated during the response-reward delay. This suggests that the activity of both these structures is related to reward anticipation. Finally, LC neurons exhibited rapid plasticity when the reward-contingency was modified. Within-trial response latencies were always shorter in LC than in PL and between-trial response adaptation in LC preceded that in PL by many trials. Identifying such temporal relationships is an essential step toward understanding how neuromodulatory inputs to forebrain networks might promote or permit experience-dependent plasticity in behavioural situations

These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory discrimination. They were injected with a beta adrenergic receptor antagonist into the PL 5 min or 2 h after training and tested 48 h later. Rats injected at 2 h showed amnesia, whereas those injected at 5 min had good retention, equivalent to saline-injected controls. Monitoring extracellular noradrenaline efflux in PL by in vivo microdialysis during the first hours after training revealed a significant increase shortly after training, with a rapid return to baseline, and then another increase around the 2-h posttraining time window. Pseudo-trained rats showed a smaller early efflux and did not show the second wave of efflux at 2 h. These results confirm earlier pharmacological and immunohistochemical studies suggesting a delayed role of noradrenaline in a late phase of long-term memory consolidation and the engagement of the PL during these consolidation processes

Cell adhesion molecule function is involved in hippocampal synaptic plasticity and is associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency at the 12-hr posttraining time in behaviours elicited by stressful stimuli, such as those associated with conditioned avoidance, water maze, and fear conditioning paradigms. To determine whether learning-induced modulation of NCAM polysialylation is limited to stressful paradigms, we employed a reward-based odour discrimination task. Animals show a rapid acquisition and recall of this task in terms of latency to identify the food-associated odour and the number of choice errors. Immunohistochemical procedures were employed to determine the change in NCAM PSA expression following task acquisition. NCAM PSA immunoreactivity in the hippocampal formation was most intense on the granule-like neurons in the infragranular zone of the dentate gyrus, and their frequency transiently increased in the 12-hr posttraining period. The nature of the transient increase in NCAM PSA-immunoreactive neurons was indistinguishable from that observed following avoidance conditioning or spatial learning, in that it occurred at the same time. The transient increase in NCAM PSA expression is suggested to facilitate dendritic elaboration in response to the acquisition of novel behavioural repertoires

The competitive antagonist 2-amino-5-phosphonoeptanoic acid (APV) was injected intracerebroventricularly to determine the involvement of NMDA receptors in different stages of memory consolidation. Subsequent experiments used local injections to determine possible sites of drug action. Rats were trained in a rapidly learned olfactory task to find palatable food in a hole in a sponge impregnated with the target odor in the presence of two other sponges with nonrewarded odors. APV injections were made intracerebroventricularly 5 min or 2 hr after the end of the training, and a retention test was given 48 hr later. The results showed that blockade of NMDA receptors immediately after training induces a profound and enduring amnesia with no effect when the treatment is delayed at 2 hr after training. To address the question of the effective sites of action of the intracerebroventricular treatment, APV injections into the hippocampus and into the prelimblic region of the frontal cortex (PLC) were made. Blockade of NMDA receptors into the PLC but not into the hippocampus impaired memory formation of the odor-reward association. The amnesia is not transient, because the retention tests were made 48 hr after training. These results underlie the role of NMDA receptors in the early stage of consolidation of a simple odor-reward associative memory and confirm the role of the PLC in the consolidation of long-term memory

The role of the central nucleus of the amygdala (CeN) in modulating output of noradrenaline in the forebrain was evaluated by recording extracellular, single-unit activity from the noradrenergic nucleus locus ceruleus (LC) during stimulation of the CeN. Short high-frequency trains (200 Hz) delivered at 800 microA in the CeN evoked phasic responses in 90% of the neurons recorded in LC. Single pulses were also effective but less reliably. The responses were complex, multiphasic with an initial latency of 10-20 msec. This early peak was diminished or, in some cases, completely blocked by local or intracerebroventricular application of the corticotrophin releasing factor antagonist alpha helical CRF (9-41). The later excitatory peak and subsequent inhibition were not effected by the drug treatment. The results underline the reciprocal functional relationship between the amygdaloid complex and the LC and suggest that the LC might be an important 'effector' of CeN activation during learning