Locus coeruleus · Grey Matter

The locus coeruleus is a small nucleus in the pons of the brainstem that supplies almost all the noradrenaline of the cortex, hippocampus, thalamus and cerebellum, and through it a few tens of thousands of neurons set the arousal of the whole brain.

Locus coeruleus. The locus coeruleus is a small nucleus in the pons of the brainstem that supplies almost all the noradrenaline of the cortex, hippocampus, thalamus and cerebellum, and through it a few tens of thousands of neurons set the arousal of the whole brain.

Its name means blue spot, from the dark pigment (neuromelanin) its cells accumulate. Stereological counts put it at about 16,000 neurons per side in older adults (range roughly 12,000 to 25,000), or a few tens of thousands in total. Each neuron has an enormously branched axon, so this handful of cells reaches nearly every region of the forebrain, releasing noradrenaline from varicosities along the axons as well as at synapses. The cells are coupled by gap junctions and tend to fire together.

It fires in two modes. In the tonic mode it fires steadily, faster with higher arousal; in the phasic mode it fires brief bursts to salient or task-relevant events. The adaptive gain theory links phasic firing to focused engagement and high tonic firing to distractibility and exploration.

It tracks state closely. LC firing is nearly silent in REM sleep, low in deep sleep and highest in alert or stressed waking; pupil size follows its activity and is used as an indirect read-out.

It receives the body's alarm. Signals from the vagus nerve, relayed through the nucleus of the solitary tract, reach it, which is how peripheral adrenaline can raise brain noradrenaline without crossing the blood-brain barrier.

It is vulnerable. It is one of the first places where tau pathology appears in Alzheimer's disease and loses neurons in Parkinson's disease.

A nucleus the size of a grain of rice turns the whole cortex up or down.

Its reach comes from axons that branch everywhere, so its state becomes the brain's state.

Questions: How can a nucleus of a few tens of thousands of neurons supply noradrenaline to the whole cortex? Stereological counts find about 16,000 neurons on each side of the human locus coeruleus (roughly 12,000 to 25,000 per side), and counts of the pigmented cells give totals of about 22,000 to 51,000. Each of these neurons has an axon that branches enormously, running through the forebrain and cerebellum and releasing noradrenaline from swellings (varicosities) all along its length, often away from classical synapses. Noradrenaline then diffuses and acts on receptors over a wide volume. The design suits a state signal: a small, internally coupled population can switch the whole brain toward alertness at once, at the cost of saying little about any specific place. What do the tonic and phasic modes of the locus coeruleus do to the cortex? In the phasic mode, moderate background firing is punctuated by brief bursts locked to task-relevant events, and the noradrenaline released then sharpens cortical responses to exactly those events. In the high tonic mode, firing is steady and elevated, bursts fade, and behaviour becomes distractible and exploratory. The adaptive gain theory of Aston-Jones and Cohen proposes that the system switches between exploiting the current task and searching for alternatives this way. Because noradrenaline raises the gain and excitability of cortical circuits, sustained high tonic output also shifts the excitation-inhibition operating point toward easier firing.