The locus coeruleus, a small nucleus located in the pons, is the main source of noradrenaline in 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. 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 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 response to stress, attention, emotion, motivation, decision making and learning and memory.
AnatomyThe locus coeruleus innervates almost the entire forebrain, with the exception of the striatum Figure 1: it projects to the entire neocortex, the thalamus, limbic structures such as the amygdala and the hippocampus, the pallidum and the cerebellum, as well as other neuromodulatory nuclei controlling the release of dopamine, acetylcholine or serotonine (B. E. Jones et al., 1977; B. E. Jones and R. Y. Moore, 1977; B. E. Jones and T. Z. Yang, 1985). The locus coeruleus receives direct excitatory and inhibitory inputs from a handful of brainstem nuclei involved in the control of primitive behavior and autonomic functions (P. H. Luppi et al., 1995) Figure 2. hypothalamus as well as forebrain structures such as the central nucleus of the amygdala, the anterior cingulate cortex and the orbitofrontal cortex. Brain stem inputs are thought to have the strongest influence on locus coeruleus neurons, because they directly target their cell bodies. The influence of forebrain inputs appears relatively weaker and/or more complex, presumably because the primary target is the pericoerulear dendritic zone, containing both locus coeruleus dendrites and local interneurons (G. Aston-Jones et al., 1991; M. Ennis et al., 1998; G. Aston-Jones et al., 2004).
- Locus coeruleus neurons fire as a function of vigilance and arousal Figure 3. 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 disappears during REM sleep (S. L. Foote et al., 1980; G. Aston-Jones and F. E. Bloom, 1981a; E. D. Abercrombie and B. L. Jacobs, 1987; R. J. Valentino et al., 1991; M. E. Page and R. J. Valentino, 1994). 3.
- Activity of locus coeruleus neurons also changes in relation to cognitive processes: reinforcement induce a transient activation (few hundreds of milliseconds) when these stimuli acquire a behavioral meaning (K. Yamamoto and N. Ozawa, 1989; S. J. Sara and M. Segal, 1991; G. Aston-Jones et al., 1994; G. Aston-Jones et al., 1997; S. Bouret and S. J. Sara, 2004; E. C. Clayton et al., 2004; S. Bouret and B. J. Richmond, 2009) Figure 5. 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 (S. Bouret and S. J. Sara, 2004; E. C. Clayton et al., 2004; S. Bouret and B. J. Richmond, 2009). This has led to the idea that LC activation could be related to decision (G. Aston-Jones and J. D. Cohen, 2005). However, the locus coeruleus could be activated in relation to covert shifts in perception, i.e. whether or not subjects are required to report these perceptual changes by performing a specific action (W. Einhauser et al., 2008). Together, these data indicate that the transient activation of locus coeruleus neurons in response to salient stimuli depends heavily upon the behavioral signification of those stimuli. This is compatible with the idea that LC activation is closely related to the cognitive processes underlying the behavioral response to these stimuli, even if the exact nature of these processes remains unclear (G. Aston-Jones and J. D. Cohen, 2005; S. Bouret and S. J. Sara, 2005; K. Doya, 2008; S. Bouret and B. J. Richmond, 2009; S. J. Sara, 2009).
In addition to these transient activations, locus coeruleus neurons also display long lasting changes in activity (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 (G. Aston-Jones et al., 1999; S. Bouret and S. J. Sara, 2004; G. Aston-Jones and J. D. Cohen, 2005; S. Bouret and S. J. Sara, 2005). 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 levels of coupling between the cells and different cognitive states. But these sustained changes could also correspond to changes in arousal, as is the case outside of cognitive tasks.
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 effects on neuronal activity and it is essential for several cognitive functions.
- Early experiments described a purely inhibitory effect of noradrenaline application on neuronal activity in the cortex, but these effects were soon discovered to be more complex (S. L. Foote et al., 1975; M. Segal and F. E. Bloom, 1976a, b; C. W. Berridge and B. D. Waterhouse, 2003). 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. 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 (A. F. Arnsten, 2000). 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 (C. W. Berridge and B. D. Waterhouse, 2003). receptive field properties of a neuron, usually an increase in selectivity)(L. M. Hurley et al., 2004). 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 (M. E. Hasselmo, 1995; M. E. Hasselmo et al., 1997). Other experiments suggest that noradrenaline modulates the temporal aspects of neuronal responses, possibly by shortening the integration time of target neurons (S. Bouret and S. J. Sara, 2002; J. C. Lecas, 2004), thereby enhancing responses to synchronized inputs and decreasing responses to less coordinated inputs Figure 6. 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 (C. W. Berridge and B. D. Waterhouse, 2003), 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 (S. J. Sara, 1985; C. W. Harley, 1987; S. J. Sara, 2000; C. W. Harley, 2004; J. L. McGaugh, 2004; S. J. Sara, 2009). The locus coeruleus also plays a major role in attention and behavioral flexibility (G. Aston-Jones et al., 1999; S. Bouret and S. J. Sara, 2005; A. J. Yu and P. Dayan, 2005). Indeed, blocking noradrenergic inputs to the forebrain, especially to the frontal lobes, induces deficits in shifting attention between task relevant stimuli, resulting in a poor adaptation to these changes. On the other hand, enhancing noradrenergic function can facilitate shift of attention when the behavioral relevance of stimuli is varied experimentally, with resultant rapid behavioral adaptation.(V. Devauges and S. J. Sara, 1990; D. S. Tait et al., 2007; J. McGaughy et al., 2008). Thus, even if to this day the relation between the influence of noradrenaline on its target neurons and behavior remains mostly speculative, converging evidence indicates that the locus coeruleus/noradrenergic system facilitates flexible interactions with the environment.
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 rapidly, especially compared to frontal and temporal association areas (Z. Liu and B. J. Richmond, 2000; S. Bouret and S. J. Sara, 2004; S. Bouret and B. J. Richmond, 2009). Moreover, during learning, the engagement of locus coeruleus neurons appears in the earliest stages of learning, usually before corresponding changes can be noticed in frontal areas (S. Bouret and S. J. Sara, 2004). 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 activity of target neurons and networks and on 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 stereotypic 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, reflexive 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 processes: 1) an enhancement of sensory and motor functions during the behavioral shift itself (G. Aston-Jones et al., 1999; C. W. Berridge and B. D. Waterhouse, 2003; G. Aston-Jones and J. D. Cohen, 2005). 2) a more generic ‘interrupt’ action, consisting in destabilizing existing activity in target areas to promote the interruption of behavior (S. Bouret and S. J. Sara, 2005; A. J. Yu and P. Dayan, 2005; S. J. Sara, 2009). 3) an enhancement of processes that immediately follow the interruption, through facilitation or stabilization of the emerging network 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, particularly the amygdala and the prefrontal cortex, which regulate the intensity of responses to salient stimuli as a function of the context. For example, when 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 intervening salient, potentially distracting stimuli, thereby preventing the interruption of ongoing behavior. Conversely, when we expect a specific stimulus, knowing that a specific response will be required (a signal for racers in a starting block), the descending influence boosts the locus coeruleus response to the expected stimulus, 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 in facilitating shifts in behavior takes place at several time scales: when the locus coeruleus activation is only transient, in response to a discrete stimulus, its effect is limited in time, allowing for a rapid reorganization of behavior following the interruption. Conversely, when 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.
- Abercrombie ED, Jacobs BL (1987) Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. I. Acutely presented stressful and nonstressful stimuli. J Neurosci 7:2837-2843.
- Arnsten AF (2000) Through the looking glass: differential noradenergic modulation of prefrontal cortical function. Neural Plast 7:133-146.
- Aston-Jones G, Bloom FE (1981a) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1:876-886.
- Aston-Jones G, Bloom FE (1981b) Nonrepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci 1:887-900.
- Aston-Jones G, Rajkowski J, Kubiak P (1997) Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task. Neuroscience 80:697-715.
- Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biological Psychiatry 46:1309-1320.
- Aston-Jones G, Zhu Y, Card JP (2004) Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: possible interneuronal pool. J Neurosci 24:2313-2321.
- Aston-Jones G, Rajkowski J, Kubiak P, Alexinsky T (1994) Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. J Neurosci 14:4467-4480.
- Aston-Jones G, Shipley MT, Chouvet G, Ennis M, van Bockstaele E, Pieribone V, Shiekhattar R, Akaoka H, Drolet G, Astier B, et al. (1991) Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology. Prog Brain Res 88:47-75.
- Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33-84.
- Bouret S, Sara SJ (2002) Locus coeruleus activation modulates firing rate and temporal organization of odour-induced single-cell responses in rat piriform cortex. Eur J Neurosci 16:2371-2382.
- Bouret S, Sara SJ (2004) Reward expectation, orientation of attention and locus coeruleus-medial frontal cortex interplay during learning. Eur J Neurosci 20:791-802.
- Bouret S, Sara SJ (2005) Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci 28:574-582.
- Bouret S, Richmond BJ (2009) Relation of locus coeruleus neurons in monkeys to Pavlovian and operant behaviors. J Neurophysiol 101:898-911.
- Clayton EC, Rajkowski J, Cohen JD, Aston-Jones G (2004) Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task. Journal of Neuroscience 24:9914-9920.
- Devauges V, Sara SJ (1990) Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav Brain Res 39:19-28.
- Doya K (2008) Modulators of decision making. Nat Neurosci 11:410-416.
- Einhauser W, Stout J, Koch C, Carter O (2008) Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry. Proc Natl Acad Sci U S A 105:1704-1709.
- Ennis M, Shipley MT, Aston-Jones G, Williams JT (1998) Afferent control of nucleus locus ceruleus: differential regulation by "shell" and "core" inputs. Adv Pharmacol 42:767-771.
- Foote SL, Freedman R, Oliver AP (1975) Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. Brain Res 86:229-242.
- Foote SL, Aston-Jones G, Bloom FE (1980) Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci U S A 77:3033-3037.
- Grant SJ, Aston-Jones G, Redmond DE, Jr. (1988) Responses of primate locus coeruleus neurons to simple and complex sensory stimuli. Brain Res Bull 21:401-410.
- Harley CW (1987) A role for norepinephrine in arousal, emotion and learning?: limbic modulation by norepinephrine and the Kety hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 11:419-458.
- Harley CW (2004) Norepinephrine and dopamine as learning signals. Neural Plast 11:191-204.
- Hasselmo ME (1995) Neuromodulation and cortical function: modeling the physiological basis of behavior. Behav Brain Res 67:1-27.
- Hasselmo ME, Linster C, Patil M, Ma D, Cekic M (1997) Noradrenergic suppression of synaptic transmission may influence cortical signal-to-noise ratio. J Neurophysiol 77:3326-3339.
- Hurley LM, Devilbiss DM, Waterhouse BD (2004) A matter of focus: monoaminergic modulation of stimulus coding in mammalian sensory networks. Curr Opin Neurobiol 14:488-495.
- Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 127:25-53.
- Jones BE, Yang TZ (1985) The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J Comp Neurol 242:56-92.
- Jones BE, Halaris AE, McIlhany M, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons. Brain Res 127:1-21.
- Lecas JC (2004) Locus coeruleus activation shortens synaptic drive while decreasing spike latency and jitter in sensorimotor cortex. Implications for neuronal integration. Eur J Neurosci 19:2519-2530.
- Liu Z, Richmond BJ (2000) Response differences in monkey TE and perirhinal cortex: stimulus association related to reward schedules. J Neurophysiol 83:1677-1692.
- Luppi PH, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience 65:119-160.
- McGaugh JL (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1-28.
- McGaughy J, Ross RS, Eichenbaum H (2008) Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 153:63-71.
- Page ME, Valentino RJ (1994) Locus coeruleus activation by physiological challenges. Brain Res Bull 35:557-560.
- Sara SJ (1985) Noradrenergic modulation of selective attention: its role in memory retrieval. Ann N Y Acad Sci 444:178-193.
- Sara SJ (2000) Retrieval and reconsolidation: toward a neurobiology of remembering. Learn Mem 7:73-84.
- Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211-223.
- Sara SJ, Segal M (1991) Plasticity of sensory responses of locus coeruleus neurons in the behaving rat: implications for cognition. Prog Brain Res 88:571-585.
- Segal M, Bloom FE (1976a) The action of norepinephrine in the rat hippocampus. IV. The effects of locus coeruleus stimulation on evoked hippocampal unit activity. Brain Res 107:513-525.
- Segal M, Bloom FE (1976b) The action of norepinephrine in the rat hippocampus. III. Hippocampal cellular responses to locus coeruleus stimulation in the awake rat. Brain Res 107:499-511.
- Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW (2007) Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur J Neurosci 25:3719-3724.
- Valentino RJ, Page ME, Curtis AL (1991) Activation of noradrenergic locus coeruleus neurons by hemodynamic stress is due to local release of corticotropin-releasing factor. Brain Res 555:25-34.
- Vankov A, Herve-Minvielle A, Sara SJ (1995) Response to novelty and its rapid habituation in locus coeruleus neurons of the freely exploring rat. Eur J Neurosci 7:1180-1187.
- Yamamoto K, Ozawa N (1989) Increased firing of locus coeruleus neurons associated with preparatory set in rats. Neurosci Lett 106:112-118.
- Yu AJ, Dayan P (2005) Uncertainty, neuromodulation, and attention. Neuron 46:681-692.