Susan J. Sara

The locus coeruleus and noradrenergic modulation of cognition

Mood, attention and motivation co-vary with activity in the neuromodulatory systems of the brain to influence behaviour. These psychological states, mediated by neuromodulators, have a profound influence on the cognitive processes of attention, perception and, particularly, our ability to retrieve memories from the past and make new ones. Moreover, many psychiatric and neurodegenerative disorders are related to dysfunction of these neuromodulatory systems. Neurons of the brainstem nucleus locus coeruleus are the sole source of noradrenaline, a neuromodulator that has a key role in all of these forebrain activities. Elucidating the factors that control the activity of these neurons and the effect of noradrenaline in target regions is key to understanding how the brain allocates attention and apprehends the environment to select, store and retrieve information for generating adaptive behaviour.

Orienting and Reorienting: The Locus Coeruleus Mediates Cognition through Arousal

Mood, motivation, attention, and arousal are behavioral states having a profound impact on cognition. Behavioral states are mediated though the peripheral nervous system and neuromodulatory systems in the brainstem. The noradrenergic nucleus locus coeruleus is activated in parallel with the autonomic system in response to biological imperatives. These responses can be spontaneous, to unexpected salient or threatening stimuli, or they can be conditioned responses to awaited behaviorally relevant stimuli. Noradrenaline, released in forebrain structures, will facilitate sensory processing, enhance cognitive flexibility and executive function in the frontal cortex, and promote offline memory consolidation in limbic structures. Central activation of neuromodulatory neurons and peripheral arousal, together, prepare the organism for a reorientation or reset of cortical networks and an adaptive behavioral response.

Sustained increase in hippocampal sharp-wave ripple activity during slow-wave sleep after learning

High-frequency oscillations, known as sharp-wave/ripple (SPW-R) complexes occurring in hippocampus during slow-wave sleep (SWS), have been proposed to promote synaptic plasticity necessary for memory consolidation. We recorded sleep for 3 h after rats were trained on an odor-reward association task. Learning resulted in an increased number SPW-Rs during the first hour of post-learning SWS. The magnitude of ripple events and their duration were also elevated for up to 2 h after the newly formed memory. Rats that did not learn the discrimination during the training session did not show any change in SPW-Rs. Successful retrieval from remote memory was likewise accompanied by an increase in SPW-R density and magnitude, relative to the previously recorded baseline, but the effects were much shorter lasting and did not include increases in ripple duration and amplitude. A short-lasting increase of ripple activity was also observed when rats were rewarded for performing a motor component of the task only. There were no increases in ripple activity after habituation to the experimental environment. These experiments show that the characteristics of hippocampal high-frequency oscillations during SWS are affected by prior behavioral experience. Associative learning induces robust and sustained (up to 2 h) changes in several SPW-R characteristics, while after retrieval from remote memory or performance of a well-trained procedural aspect of the task, only transient changes in ripple density were induced.

Elevated Sleep Spindle Density after Learning or after Retrieval in Rats

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 (∼25%) and the time window of maximal effect (∼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.

Noradrenergic Neurons of the Locus Coeruleus Are Phase Locked to Cortical Up-Down States during Sleep

Nonrapid eye movement (NREM) sleep is characterized by periodic changes in cortical excitability that are reflected in the electroencephalography (EEG) as high-amplitude slow oscillations, indicative of cortical Up/Down states. These slow oscillations are thought to be involved in NREM sleep-dependent memory consolidation. Although the locus coeruleus (LC) noradrenergic system is known to play a role in off-line memory consolidation (that may occur during NREM sleep), cortico-coerulear interactions during NREM sleep have not yet been studied in detail. Here, we investigated the timing of LC spikes as a function of sleep-associated slow oscillations. Cortical EEG was monitored, along with activity of LC neurons recorded extracellularly, in nonanesthetized naturally sleeping rats. LC spike-triggered averaging of EEG, together with phase-locking analysis, revealed preferential firing of LC neurons along the ascending edge of the EEG slow oscillation, correlating with Down-to-Up state transition. LC neurons were locked best when spikes were shifted forward ∼50 ms in time with respect to the EEG slow oscillation. These results suggest that during NREM sleep, firing of LC neurons may contribute to the rising phase of the EEG slow wave by providing a neuromodulatory input that increases cortical excitability, thereby promoting plasticity within these circuits.

Commentary — reconsolidation: Strengthening the shaky trace through retrieval

Retrieval of fear conditioning turns memory into a labile state sensitive to disruption. Here, I raise the issue that in addition to aversive, amygdala-dependent memories, other forms of memory are susceptible to the same effect, and I review evidence indicating that neuromodulation may have a significant influence on the reconsolidation process.

Memory retrieval enhanced by amphetamine after a long retention interval

Four experiments investigated the effects of amphetamine on retrieval of a “forgotten” maze task. Rats were trained to run a six-unit spatial discrimination maze for food reward. After a 3-week training to test interval, control animals showed significant forgetting as measured by errors, run time, and retracings. Treatments with amphetamine 20 min before the retention test alleviated this forgetting, in that treated animals had a performance which was not different from the last training trial. The effect was dose dependent, effective doses being 0.25 and 0.50 mg/kg; larger doses were ineffective. There was no state-dependent retrieval effect; animals which showed facilitation under amphetamine treatment, continued to perform well when retested without the drug, 24 hr later. A final experiment showed that there was no effect on acquisition, whether the treatment was given before the first, second, or third acquisition trial. The results are discussed in terms of the possible role of catecholamines, central or peripheral, in memory retrieval processes.

Vasopressin accelerates appetitive discrimination learning and impairs its reversal.

Rats were trained in a semi-automated Y maze to find food at the end of the lighted arm. Those treated with 10 μ g lysine vasopressin, 90 min before training learned the response to a 9 10 correct choice criterion significantly faster than saline treated animals. There was no difference in rate of forgetting between the treatment groups, as evidenced by a retention test, 3 weeks after training. There was no direct effect of vasopressin on retrieval, since animals treated before the retention test performed at the same level as non treated animals. Finally, vasopressin impaired reversal from light to dark. In a second experiment, the acquisition facilitation seen in Exp. I was replicated, but there was no effect of the treatment on animals trained to dark SD. However, the impairment seen in Exp. I when vasopressin treated animals, trained to light, were reversed to dark, was replicated in this experiment in animals trained to dark and reversed to light. Previous demonstrations of vasopressin facilitation of learning and memory have, with few exceptions, relied on shock avoidance tasks. The present experiments demonstrate a reliable facilitation of appetitive learning by vasopressin. The fact that vasopressin impairs reversal may be due to an increased tendency to perseverate.

Reactivation, Retrieval, Replay and Reconsolidation in and Out of Sleep: Connecting the Dots

The neurobiology of memory has taken on a new look over the past decade. Re-discovery of cue-dependent amnesia, wide availability of functional imaging tools and increased dialog among clinicians, cognitive psychologists, behavioral neuroscientists, and neurobiologists have provided impetus for the search for new paradigms for the study of memory. Memory is increasingly viewed as an open-ended process, with retrieval being recognized as an intricate part of the encoding process. New memories are always made on the background of past experience, so that every consolidation is, in fact reconsolidation, serving to update and strengthen memories after retrieval. Spontaneous reactivation of memory circuits occurs during sleep and there is converging evidence from rodent and human studies that this is an important part of the extended off-line memory processing. The noradrenergic neuromodulatory system is engaged at retrieval, facilitating recall. The noradrenergic system is also activated during sleep after learning and noradrenergic neurons fire in concert with cortical oscillations that are associated with reactivation of memory circuits. We suggest that the noradrenergic system and perhaps other neuromodulatory systems, may be a key to linking off-line memory reactivation, retrieval, and memory reconsolidation processes at both synaptic and systems levels, in and out of sleep.

Reticular stimulation facilitates retrieval of a ‘forgotten’ maze habit

Rats tested 25 days after training in a complex maze showed significant forgetting. Stimulation of the mesencephalic reticular formation immediately prior to retention testing facilitated performance in that stimulated rats made fewer errors (but did not run faster) than non-stimulated controls. Rats exposed to a contextual cue as a reminder before testing ran faster and made fewer errors than controls. Results are discussed in terms of forgetting being due to retrieval failure, and the reticular stimulation facilitating retrieval of information concerning the spatial configuration of the maze.