Locus coeruleus: a new look at the blue spot

Abstract

The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.

Fig. 1 ∣. The blue spot: past discoveries and future horizons.

The discovery of the existence of monoamine-containing neurons in the CNS by Dahlstroem and Fuxe in 1964 (REF.) inspired subsequent systematic research on locus coeruleus (LC) structure and function. Use of the available neuroscience methodologies allowed many pioneering discoveries and influential theories of function (second panel). Unprecedented technological advances in recent years have been a catalyst for obtaining new results that confirmed, but also challenged, the existing knowledge about the LC-noradrenaline (NA) system (third panel). Newly revealed complexity of the organization of the LC-NA system has raised many new questions (fourth panel), opening new vistas for future research. fMRI, functional MRI.

Fig. 2 ∣. Evolving views of the LC synaptic architecture and functional organization.

a ∣ Historically, the locus coeruleus (LC) had been thought to contain functionally homogeneous neurons (indicated here by a uniform blue colour) whose axons extensively collateralize and indiscriminately innervate functionally diverse terminal fields. b ∣ More recently, several studies^,,- have shown that the axons of LC neurons are less extensive than had previously been recognized, and instead innervate anatomically and functionally distinct targets. In the schematic, each colour represents a population of LC neurons that projects strongly to a preferred terminal field, including olfactory bulb (medium blue), frontal cortex (medium green), visual cortex (light blue), thalamus and midbrain (red), cerebellum (light green) and spinal cord (pink). Note that this schematic is illustrative only and that there are likely more than six efferent LC pathways. Evidence also suggests that LC neurons also innervate terminal fields beyond their preferred targets, though less densely. c–f ∣ The organization of the presynaptic inputs to LC is less clear. Early studies suggested that all LC neurons were innervated by a limited set of common afferents, which then went on to innervate all regions of the CNS (part c). Another possibility is that a common set of afferents equally innervate all LC neurons, which then transmit information in a selective way to specific terminal fields (part d). A more complex arrangement would have unique afferents linked to discrete LC neurons that preferentially innervate functionally distinct terminal fields, such that there is discrete coding of information as it passes through the nucleus (part e). Another possibility is that the LC is organized such that some afferents innervate all of the LC, and so can modulate the activity of the nucleus as a whole, while others are more discrete and allow for point-to-point communication. The same holds true for LC efferents: some LC neurons have a preferred terminal field that they densely innervate, while others broadly innervate vast expanses of the CNS. Under this model, the LC is capable of globally broadcasting information to all its terminals simultaneously when its broad afferents are engaged. In some circumstances, however, only discrete afferents may be engaged, to allow for discrete coding of information by LC and transmission only to specific terminals (part f). NA, noradrenaline.

Fig. 3 ∣. GANE release creates local NA ‘hot spots’ and alters network processing: the network GANE model.

a ∣ A noradrenaline (NA) ‘hot spot’. Local spillover glutamate (blue dots) from active glutamate terminals (step 1) interacts with depolarized NA varicosities. These NA varicosities (pink) are depolarized by locus coeruleus (LC) activation. Spillover glutamate acting on three kinds of glutamate receptors — NMDA receptors (NMDAR), AMPA receptors (AMPAR), and metabotropic glutamate receptors 1/5 (mGluR1/mGluR5) — may increase NA release from these varicosities (green dots; step 2). β-Adrenoceptors on glutamate terminals can promote additional glutamate release, in a positive feedback loop. Spillover glutamate also recruits astrocytes (step 3) to release the NMDA co-agonists serine and glycine (grey dots) and additional, astrocyte-sourced glutamate (blue dots). Finally, on the postsynaptic glutamate neuron, local NA activates higher-affinity α2- and α1-receptors. If NA concentrations are sufficiently high, NA also recruits the lower-affinity β-adrenoreceptors to promote long-term potentiation (LTP) at those glutamate synapses. To generate LTP, a high level of β-adrenoreceptor activation is needed, because lower levels of β-adrenoreceptor activation promote long-term depression, attenuating the input strength. Failure to recruit β-adrenoreceptors will leave the glutamate circuitry unchanged. Increased local NA can also act in an autocrine fashion on α2-and β-adrenoreceptors expressed on the NA varicosities, modulating further NA release. β-Adrenoreceptor activation would also increase NA release in a positive feedback loop. b ∣ The system-wide effects of glutamate amplification of noradrenaline (GANE) interact with local ‘hot spot’ effects. Salience-evaluating structures, such as the anterior cingulate cortex and insula, recruit LC firing in order to enable NA to modulate ongoing processing at multiple levels of brain function. Local glutamate–NA memory-enhancing effects occur in parallel with more broad-scale suppression, as NA recruits lateral and auto-inhibitory processes that suppress weaker glutamate signals in lower-priority processing pathways. These noradrenergic mechanisms lead to ‘winner-take-more’ and ‘loser-take-less’ outcomes in perception and memory under arousal. For example, if the girl in the yellow raincoat has high priority at the moment, either because of her perceptual salience or because of a goal (for example, rooting for her team), memory for her should be enhanced if something else (for example, loud thunder) induces arousal at that moment, whereas the peripheral inputs are more likely to be forgotten. High-priority input interacts with LC-induced arousal and recruits resources and networks to create new memory circuits, whereas lower-priority input is unsupported. Part a adapted with permission from REF., Cambridge University Press. Part b image courtesy of David Clewett, UCLA.