Locus coeruleus
From Scholarpedia
| This article has not been peer-reviewed or accepted for publication yet; It may be unfinished, contain inaccuracies, or unapproved changes. | ||||||||||||||||||||
Author: Dr. Sebastien Bouret, NIMH/NIH, Bethesda, MD, USA
Author: Dr. Susan J. Sara, CNRS, Collège de France
Dr. Sebastien Bouret accepted the invitation on 13 January 2009 (self-imposed deadline: 13 July 2009).
Dr. Sebastien Bouret, NIMH/NIH, Bethesda, MD, USA, was invited on 13 January 2009.
[THIS IS A PRELIMINARY VERSION, 08/10]
The locus coeruleus, a small nucleus located in the pons, is the main source of noradrenaline to the forebrain. Together with other nuclei located in the antero-dorsal part of the brain stem, it belongs to what used to be described as the ‘ascending reticular activating system’, an area critical for arousal and wakefulness. If the locus coeruleus could account for some of these functions, our understanding of its role has been refined over the last few decades. Locus coeruleus neurons have extremely wide projections and they are innervated by only a few brain stem nuclei and forebrain areas. The activity of locus coeruleus neurons varies not only with arousal but also with specific cognitive processes, resulting in concerted release of noradrenaline in their multiple target areas, and very complex effects depending upon local parameters. This key neuromodulatory system is currently thought to be critical for numerous functions including stress, attention, emotions, motivation, decision making or learning and memory.
Contents |
[edit]
Anatomy
[edit]
Physiology
- locus coeruleus neurons fire in relation to vigilance and arousal. They display a slow irregular firing during quiet wakefulness and a sustained activation if the subject is stressed or excited. Their firing decreases markedly during slow-wave sleep and virtually disapears during REM sleep (Aston-Jones, Valentino, Jouvet). In addition to these sustained, state-related changes in activity, locus coeruleus neurons also display a transient activation (hundreds of millisecond) in response to salient stimuli, ie stimuli that are behaviorally relevant and naturally evoke a behavioral reaction: intense stimuli (flashes of light, intense tones), aversive stimuli (such as foot chocks) or novel stimuli (Grant, Aston-Jones, Sara). The transient locus coeruleus activation is closely associated with the overt reaction to the salient stimulus (autonomic response to stressfull stimuli, orienting response to novel or intense stimuli) and locus coeruleus responses disappear when the behavioral responses habituates (ref, ref).
Figure 3: Activity of an LC neuron in a behaving rat. The firing rate decreases when the animal becomes drowsy
Figure 4: Activity of an LC neuron at the onset of a light, which evokes an orienting response from the rat - Activity of locus coeruleus neurons also changes in relation to cognitive processes: when subjects perform cognitive tasks in laboratory settings, locus coeruleus neurons are activated by task relevant stimuli: images, tones or odors that predict an appetitive or aversive reinforcement induce a transient activation (few hundreds of milliseconds) when these stimuli acquire a behavioral meaning (Aston-Jones, Sara &Segal, Bouret & Sara, Bouret & Richmond). Importantly, the timing of locus coeruleus activation in these tasks is more tightly associated with overt behavioral responses to these stimuli than to their appearance. Nevertheless, the locus coeruleus could be activated in relation to covert shifts in perception, i.e. whether or not subjects need to report these perceptual changes by performing a specific action (Carter). Together, these data indicate that the transient activation of locus coeruleus neurons in response to salient stimuli depends heavily upon their behavioral signification. This is compatible with the idea that LC activation is closely related to the cognitive processes underlying the behavioral response to these stimuli (Aston-Jones & Cohen, Bouret & Sara).
Figure 5: task related activity in monkeys: LC activation is more closely related to the behavioral response (t=0, vertical line) than to the instruction (go signal, green symbols)
In addition to these transient activations, locus coeruleus neurons also display long lasting changes in activity (over seconds or more): their firing rate tends to decrease when animals engage in a complex task and await-task relevant stimuli. By contrast, their firing rate increases when animals fail to concentrate, disengage from the task at hand and ignore the stimuli (Aston-Jones, Bouret & Sara). These sustained changes in activity are sometimes referred to as ‘phasic’ and ‘tonic’ modes (for sustained low and high firing rates, respectively), thought to correspond to different level of coupling between the cells and different cognitive states (Aston-Jones & Cohen). But these sustained changes could also correspond to changes in arousal, as it is the case outside of cognitive tasks.
[edit]
Influence on target neurons and behavior
- The activation of locus coeruleus neurons provides a central command that increases noradrenaline release in its multiple target regions, although noradrenaline release by locus coeruleus terminals is also controlled by local mechanisms. Noradrenaline has complex neuromodulatory effect on neuronal activity and it is essential for several cognitive functions.
- Early experiments described a purely inhibitory effect of locus coeruleus stimulation or noradrenaline application on neuronal activity, especially in the cortex, but these effects were soon discovered to be more complex (ref). The action of noradrenaline on target neurons varies enormously in different brain regions and as a function of the concentration of noradrenaline, presumably because of differences in the proportion of the different types of receptors (alpha 1, alpha 2 and beta). For instance, when noradrenaline levels are low, it preferentially acts on high affinity alpha 2 receptors in prefrontal cortex to improve executive functions (Arnsten). Higher levels of noradrenaline recruit alpha 1 and beta receptors, resulting in an impairment of executive functions and presumably in an improvement in sensory processing in posterior brain areas (Arnsetn, Waterhouse). Indeed, the activation of locus coeruleus or direct application of noradrenaline tends to have a more potent inhibitory action on spontaneous activity than on activity evoked by a stimulus, which led to the idea that noradrenaline improved the so called ‘signal to noise ratio’ of evoked responses in sensory cortices. Other effects of noradrenaline on sensory neurons include ‘gating’ (allowing an otherwise subthreshold response to weak stimuli) and ‘tuning’ (modification of the receptive field properties of a neuron, usually an increase in selectivity) (Waterhouse, Hurley et al). In another set of experiments conducted in the olfactory cortex, noradrenaline was shown to decrease cortico-cortical inputs more than subcortical inputs form the olfactory bulb, suggesting that noradrenaline enhances bottom-up inputs (coming from sensory organs) at the expense of top down (cortico-cortical) inputs (Hasselmo). Other experiments suggest that noradrenaline modulates the temporal aspects of neuronal responses (Bouret & Sara, Lecas), possibly by shortening the integration time of target neurons, thereby enhancing responses to synchronized inputs and decreasing responses to less coordinated inputs(ref). So if it is clear that a single activation of locus coeruleus can influence its target areas within a few hundred milliseconds, the nature of that influence is still unclear and the relation between these neuronal effects and perception remains mostly hypothetical.
- In behaving animals, locus coeruleus activation promotes high levels of vigilance and arousal (Berridge) but it is also involved in specific cognitive functions. The noradrenergic system is critical for learning and memory, especially for emotional events, presumably via long term cellular and molecular effects that underlie neural plasticity (Harley, Sara, McGaugh). The locus coeruleus also plays a major role in attention and behavioral flexibility. Indeed, blocking noradrenergic inputs to the forebrain, especially to the frontal lobes, induces deficits in shifting attention between task relevant stimuli: subjects fail move their attention between features of their environment when the behavioral relevance of these features is varied experimentally, resulting in a poor adaptation to these changes (Devauges & Sara, Tait et al, McGaughy). Thus, even if to this day the relation between the influence of noradrenaline on its target neurons and behavior remains mostly speculative, converging evidences indicate that the locus coeruleus facilitates flexible interactions with the environment.
[edit]
Functions of the locus coeruleus
- The primary function of the locus coeruleus is to regulate the amount of noradrenaline in the forebrain. Thus, at a behavioral or systems level, the function of the locus coeruleus critically depends upon the dynamic interaction between the released noradrenaline and neuronal activity in its multiple target areas. Data available so far indicate that locus coeruleus activation in response to salient stimuli occurs very fast, especially compared to frontal and temporal association areas (Bouret & Sara). Moreover, during learning, the activation of locus coeruleus neurons appears in the earliest stages of learning, sometimes before corresponding changes can be noticed in frontal areas. Since locus coeruleus activation results in a massive release of noradrenaline in target structures and a single locus coeruleus activation influences target areas within a few hundreds of milliseconds, these transient responses to salient stimuli are in a position to modulate activity in target areas as the animal adjusts its behavior to cope with the situation. Of course sustained locus coeruleus activation, resulting in stronger and longer lasting release of noradrenaline, also has a significant impact on neuronal activity and behavior. Given the known effect of noradrenaline on cognitive flexibility, one can speculate on the function of the locus coeruleus/noradrenaline system at a systems and behavioral level:
- The stereotype condition of locus coeruleus activation, which can be described in a vast majority of species, is the orienting response: After a salient stimulus (eg a loud sound), we interrupt whatever we were doing before, orient to the stimulus, and then analyze the situation to initiate a new course of action (or possibly resume what we were doing before the stimulus). The activation of locus coeruleus is tightly associated with primitive behavioral responses to salient stimuli, which is in line with its strong innervation by brainstem nuclei.
- In primitive species, things could be relatively simple: salient stimuli induce an activation of autonomic centers and other phylogenetically old brain structures to trigger innate, stereotyped, behavioral responses, which have been selected by evolution to cope with many emergency situations. This is a simple case of behavioral shift. The associated activation of locus coeruleus could facilitate behavioral adaptation through several (non exclusive) processes: 1) an enhancement of sensory and motor functions during the behavioral shift itself (Aston-Jones & Cohen, Waterhouse). 2) a more generic ‘interrupt’ action, consisting in destabilizing existing activity in target areas to promote the interruption of behavior (Bouret & Sara, Yu & Dayan). 3) an enhancement of processes that immediately follow the interruption, through facilitation or stabilization of the emerging activity. In any case, the locus coeruleus activation participates in the behavioral adjustment to the salient stimulus through a widespread action on its target structures.
- In more complex species such as mammals, things could be more complicated: locus coeruleus neurons are also innervated by forebrain inputs (such as the amygdala and the prefrontal cortex) which regulate the intensity of responses to salient stimuli as a function of the context. For example, if we need to focus on a task at hand and specifically do not want to be distracted, (eg trying to remember a phone number to dial it moments later), the descending influence of forebrain areas attenuates the locus coeruleus response to salient, potentially distracting stimuli, thereby preventing the interruption of ongoing behavior. Conversely, if we expect a specific stimulus, knowing that a specific response will be required (bang for racers in starting blocks), the descending influence boosts the locus coeruleus activation, thereby facilitating behavioral adjustment. Again, behavioral adaptation includes not only motor but also sensory, emotional and executive function, which can all be regulated by locus coeruleus activation.
- This action of the locus coeruleus/noradrenergic system to facilitate shifts in behavior could take place at several time scales: if the locus coeruleus activation is only transient, in response to a discrete stimulus, its effect would be limited in time, allowing for a rapid reorganization of behavior following the interuption. Conversely, if the locus coeruleus activation is more prolonged, for instance in cases of extreme stress, subjects get constantly distracted: they keep altering their course of action (and/or focus of attention) so frequently (every few seconds) that overall behavior becomes disorganized, unfocused. Conversely, when locus coeruleus neurons display lasting decreases in activity (during sleep or awaiting for a stimulus), behavior is very stable and constant over time.
