Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.

The locus coeruleus (LC) was first described by Vicq d’Azyr (1786). Reil subsequently specified it as a bluish-black mark on the floor of the IV ventricle and was named so by Wenzel and Wenzel, who defined it as a collection of pigmented neurons in the dorsolateral tegmentum of the human brain. It was due to the efforts of Russell in 1955, in studying the comparative anatomy of LC using Nissl staining, that it was identified as a distinct nuclear entity, unlike earlier reports where its cells were confused with the mesencephalic tract-associated nucleus of the trigeminal nerve noted in comparable locations in many animal studies. LC has been studied in different animal species, such as rat, cat, dog, sheep, bat, rabbit, primates, horse, sea lion and owl, the most common model being the rat. It was not until the discovery by Dahlström and Fuxe in 1964, using the Falck–Hillarp histofluorescence technique, that the nucleus garnered attention. Several Swedish scientists using small electrolytic lesions in Wistar rats provided an overview of the projections, including their fusion with other ponto-medullary noradrenaline (NA) projections to terminate in the hypothalamus and elsewhere. Further, in 1969, Loizou received tremendous appreciation for his work on the central aminergic system using the histofluorescence method to demonstrate widespread and diffuse projections to different parts of the central nervous system (CNS). Subsequently, several authors applied anterograde and retrograde tract tracing as well as dopamine β-hydroxylase (DBH) staining and reported the presence of a dense pack of norepinephrine (NE) neurons uniquely in the LC, with their extensive projections in the neuraxis. Several studies on animal models have construed that the anterior and middle segments of the nucleus control attention and diurnal rhythms via the cortex-directed and hippocampus-directed projections, while the posterior aspect governs respiratory, cardiac and gastric activities. By 1980, NA was confirmed to be the primary neurotransmitter, thus consolidating its importance in CNS functions. These classical studies laid emphasis on a better understanding of the normal physiology, anatomical projections and functions of this tiny, underexplored region in normal ageing, neurodegeneration and psychiatric illnesses.