Fig 1. Hypothesis for selective locus ceruleus (LC) neuronal toxicity causing focal nervous system pathology, using multiple sclerosis as an example.

(1) Normal LC neurons (blue) maintain the integrity of the blood-brain barrier of small blood vessels (BV) in the central nervous system via their output of noradrenaline. (2) On initial exposure to a circulating toxicant, the toxicant is taken up selectively by some LC neurons (red) only. A subsequent decrease in noradrenaline output impairs the blood-brain barrier of blood vessels innervated by these toxicant-containing LC neurons. (3) On further exposure to the same (or a different) circulating toxicant, the toxicant passes through the damaged blood-brain barrier. (4) Depending on the type of toxicant exposure and the individual’s genetic susceptibility, tissue damage results from several pathological mechanisms, including free radical generation, neuroinflammation, or apoptosis. Here, a toxicant penetrating a damaged blood-brain barrier has induced axonal demyelination, resulting in a multiple sclerosis plaque.