Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression

Abstract

A quantitative study of the morphology and distribution of norepinephrinergic neurons in the human locus coeruleus (LC) is given for normal young and older adult brain. Norepinephrine (NE)-producing neurons are identified by immunocytochemistry of two NE biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), visualized by the peroxidase-antiperoxidase and immunogold-silver-staining methods. TH and DBH immunoreactions yield equivalent results. Both immunocytochemical visualization methods allow detailed analysis of neuronal morphology. The neurons of the human LC fall into four classes: large multipolar neurons with round or multiangular somata, large elliptical "bipolar" neurons, small multipolar neurons, and small ovoid "bipolar" neurons. Though most of the neurons contain neuromelanin pigment, some larger neurons lack pigmentation. Dendritic arborization of all neurons is extensive. Computer-assisted quantitative measurements of the parameters somatic size, dendritic arbor length, surface area, and volume are given. Somatic areas of LC neurons of all four classes are decreased in older adult brain, but dendritic arborization is equally extensive as in the younger. The rostrocaudal length of the LC is approximately 15 mm, and no age-dependent decrease is observed. Computer-assisted mapping of immunoreactive neurons and three-dimensional reconstruction allow division of the LC into rostral, middle, and caudal parts with characteristic distribution of neurons. Small neurons predominate in all parts, but the relative contribution of larger cells decreases in a rostrocaudal direction. A cell loss of 27-37% occurs in older adult brains and to 55% in the brain of a chronically depressed patient without dementia. Cell loss is highest in the rostral part, lower in the middle, and absent in the caudal part, and more small cells are lost than larger ones.

Pharmacology and Distribution of Norepinephrine Transporters in the Human Locus Coeruleus and Raphe Nuclei

“…Iversen et al (1983) have shown that counting locus coeruleus neurons that contain neuromelanin and those that contain dopamine-␣-hydroxylase gives the same number of cell counts in the human brain. Other studies have demonstrated similar results by counting tyrosine hydroxylase-immunoreactive neurons and the number of cells containing neuromelanin pigment in the same brains (Mann and Yates, 1979;Baker et al, 1989;Chan-Palay and Asan, 1989;Blanchard et al, 1993). Tyrosine hydroxylaseimmunoreactive cells that do not contain neuromelanin have been reported (Chan-Palay and Asan, 1989) in the human locus coeruleus, but these neurons occur in a small region of the locus coeruleus rostral to the frenulum, an area where cell counts and binding were not compared in the present study.…”

“…Neuromelanin pigment appears as very dark granules and is characteristic of all catecholamine-containing neurons in humans (Bogerts, 1981). Neuromelanin may be a waste product resulting from oxidative catabolism of catecholamine and in locus coeruleus neurons appears to be colocalized with tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (Mann and Yates, 1979;Baker et al, 1989;Chan-Palay and Asan, 1989). Iversen et al (1983) have shown that counting locus coeruleus neurons that contain neuromelanin and those that contain dopamine-␣-hydroxylase gives the same number of cell counts in the human brain.…”

Brainstem Activity Predicts Attachment-Related Anxiety

“…The LC is the site of synthesis and release of the neurotransmitter norepinephrine, and the neurons of the LC are important in a variety of cognitive, affective, and other behavioral functions, as well as associated clinical dysfunctions (e.g., depression, anxiety, sleep and circadian disorders [52]). Compared to healthy controls, depressed individuals display reduced gray matter density in this region [53][54][55]. The LC is also one of the primary sites mediating the stress response as well as a site of action of anti-depressant drugs [56].…”

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

“…Agingrelated decline in motor function has been associated with noradrenergic (NE) deficits (Chan-Palay and Asan, 1989;Gesi et al, 2000). Furthermore, 18-month-old GDNF ϩ/Ϫ mice have lower NE concentrations and morphological alterations of NE cell bodies in the locus ceruleus, lower NE transporter activity in the cerebellum and brainstem, and fewer TH-positive fibers in the hippocampus, cerebellum, and frontal cortex compared with age-matched WT mice (Zaman et al, 2003).…”