Locus Coeruleus

Anatomy

• A thin column of cells about 15 mm long in the dorsolateral pontine tegmentum, near the floor of the fourth ventricle; named for the bluish color given by neuromelanin pigment.
• Only a few tens of thousands of noradrenergic neurons on each side; yet their axons branch into almost every region of the brain.
• Output: cortex, hippocampus, amygdala, thalamus and hypothalamus (dorsal noradrenergic bundle); cerebellum and spinal cord. Little contribution to the striatum.
• Input: nucleus paragigantocellularis and prepositus hypoglossi in the medulla, prefrontal cortex (ACC, OFC), central nucleus of the amygdala (CRF), lateral hypothalamus (orexin).

Functions

• Level of wakefulness and arousal: active when awake, slows in NREM sleep and falls nearly silent in REM sleep.
• Attention: phasic responses support focusing on a task, high tonic activity supports distractibility and exploration (adaptive gain theory; Aston-Jones and Cohen, 2005).
• Prefrontal cortex: moderate noradrenaline strengthens working memory via α2A receptors; the high levels of stress impair it via α1 and β receptors (an inverted-U relationship).
• Stress response: activated by CRF from the amygdala, it increases vigilance and sympathetic arousal.
• Strengthens the consolidation of emotionally important events (noradrenaline in the amygdala and hippocampus).
• Descending pain inhibition: noradrenergic fibers to the spinal cord suppress pain transmission.

Connections and chemistry

• LC → cortex, hippocampus, amygdala, thalamus (dorsal noradrenergic bundle)
• LC → cerebellum and spinal cord (descending pain inhibition)
• Central nucleus of the amygdala → LC (CRF; stress)
• Prefrontal cortex (ACC, OFC) → LC (top-down control)
• Lateral hypothalamus → LC (orexin; wakefulness)
• Noradrenaline: α1, α2A and β receptors

Development

Developmental course through childhood and adolescence.

• LC neurons form early in embryonic life; noradrenaline also acts as a signal that influences neuronal migration and synapse formation during cortical development (animal studies).
• In animal models, early-life stress can permanently increase the LC’s sensitivity to CRF and its stress reactivity.
• LC neuron dysfunction has been shown in mouse models of Rett syndrome.

Clinical

• ADHD: atomoxetine (a noradrenaline reuptake inhibitor), guanfacine and clonidine (α2A agonists) support prefrontal function; stimulants also raise noradrenaline.
• Anxiety and panic: increased noradrenergic reactivity; the α2 antagonist yohimbine can trigger panic-like symptoms in people with panic disorder.
• PTSD: hyperarousal, exaggerated startle, nightmares. The α1 antagonist prazosin has been used for nightmares but was not superior to placebo in a large trial (Raskind et al., 2018).
• Depression: antidepressants with noradrenergic action (SNRIs, bupropion).
• Opioid withdrawal: LC hyperactivity contributes to autonomic withdrawal symptoms; clonidine and lofexidine ease them.

Treatment

This region from the perspective of medication, psychotherapy and neuromodulation. Letter badges are evidence levels.

• Atomoxetine: a noradrenaline reuptake inhibitor; raises prefrontal noradrenaline and dopamine (in the prefrontal cortex, dopamine is also cleared by the noradrenaline transporter). A non-stimulant option in ADHD. A
• Clonidine and guanfacine (α2A agonists): clonidine reduces LC firing; guanfacine acts mainly by closing HCN channels on prefrontal spines, strengthening the working memory network (Wang et al., 2007). Effective in ADHD. A Evidence for tics is weaker: clonidine has positive trials, while extended-release guanfacine did not outperform placebo in a small paediatric trial (Murphy et al., 2017). B
• Lofexidine and clonidine: reduce autonomic symptoms from LC hyperactivity in opioid withdrawal; lofexidine is FDA-approved in adults (2018). A
• Prazosin (α1 antagonist): widely used for PTSD nightmares, but not superior to placebo in a large multicenter trial (Raskind et al., 2018). B
• Propranolol (β antagonist): used for the bodily symptoms of performance anxiety; its use to block reconsolidation of traumatic memories is experimental. C

Assessment

Neuropsychological tasks and measures that probe this region's function.

• Pupillometry: pupil diameter and phasic pupil responses are indirect indices of LC activity (research)
• Oddball paradigm and the P3 component: linked to the phasic LC response (Nieuwenhuis et al., 2005)
• Continuous performance tests and reaction time variability: regulation of arousal and attention
• LC signal intensity with neuromelanin-sensitive MRI (research)

Lesions and damage

Clinical findings expected with damage or dysfunction.

• Isolated LC lesions are rare in humans; in animals, wakefulness, reorienting of attention and the stress response are impaired.
• Dopamine β-hydroxylase deficiency (noradrenaline cannot be made): severe congenital orthostatic hypotension, ptosis, nasal congestion.
• In Parkinson’s and Alzheimer’s disease, LC neurons are lost early in the disease (adults).

In the model

How this structure is defined in the 3D model, and the data source.

Harvard AAN v2.0 right and left LC labels (see the PAG note for the transfer). Because it is only a few voxels wide at 1 mm resolution, the surface was smoothed while preserving volume; fine shape detail is approximate.

References

Full citations for the card; links go to the paper (DOI) or a PubMed search.

1. Wang M et al. Cell 2007. Search PubMed
2. Raskind MA et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med 2018 (kartta zaten vardı). Search PubMed