Locus coeruleus

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Locus coeruleus
HE-LFB stain.
Details
Identifiers
Latinlocus caeruleus ("blue place")
MeSHD008125
NeuroNames583
NeuroLex IDbirnlex_905
TA98A14.1.05.436
A14.1.05.706
TA25944
FMA72478
Anatomical terms of neuroanatomy]
Locus coeruleus and its influence pathways

The locus coeruleus (

reticular activating system
.

The locus coeruleus, which in Latin means "blue spot", is the principal site for brain synthesis of norepinephrine (noradrenaline). The locus coeruleus and the areas of the body affected by the norepinephrine it produces are described collectively as the locus coeruleus-noradrenergic system or LC-NA system.[3] Norepinephrine may also be released directly into the blood from the adrenal medulla.

Anatomy

HE-LFB stain.
Locus coeruleus highlighted in green.

The locus coeruleus (LC) is located in the posterior area of the rostral

neurons. Melanin granules inside the neurons of the LC contribute to its blue colour. Thus, it is also known as the nucleus pigmentosus pontis, meaning "heavily pigmented nucleus of the pons." The neuromelanin is formed by the polymerization of norepinephrine and is analogous to the black dopamine-based neuromelanin in the substantia nigra
.

In adult humans (19-78) the locus coeruleus has 22,000 to 51,000 total pigmented neurons that range in size between 31,000 and 60,000 μm3.[4]

Connections

The projections of this nucleus reach far and wide. For example, they innervate the

telencephalon, and the cortex. The norepinephrine from the LC has an excitatory effect on most of the brain, mediating arousal
and priming the brain's neurons to be activated by stimuli.

As an important

cingulate gyrus and the amygdala also innervate the LC, allowing emotional pain and stressors to trigger noradrenergic responses. The cerebellum and afferents from the raphe nuclei also project to the LC, in particular the pontine raphe nucleus and dorsal raphe nucleus
.

Inputs

The locus coeruleus receives inputs from a number of other brain regions, primarily:

Outputs

The projections from the locus coeruleus consist of neurons that utilize norepinephrine as their primary neurotransmitter.[5][6] These projections include the following connections:[5][6]

Function

It is related to many functions via its widespread projections. The LC-NA system modulates cortical, subcortical, cerebellar, brainstem, and spinal cord circuits. Some of the most important functions influenced by this system are:[7][8]

The locus coeruleus is a part of the

reticular activating system, and is almost completely inactivated in rapid eye movement sleep.[13]

Pathophysiology

The locus coeruleus may figure in

norepinephrine-dopamine reuptake inhibitors (bupropion) are believed to show efficacy by acting upon neurons
in this area.

Research continues to reveal that norepinephrine (NE) is a critical regulator of numerous activities from stress response, the formation of memory to attention and arousal. Many neuropsychiatric disorders precipitate from alterations to NE modulated neurocircuitry: disorders of affect, anxiety disorders, PTSD, ADHD and Alzheimer's disease. Alterations in the locus coeruleus (LC) accompany dysregulation of NE function and likely play a key role in the pathophysiology of these neuropsychiatric disorders.[15]

In stress

The locus coeruleus is responsible for mediating many of the sympathetic effects during stress. The locus coeruleus is activated by stress, and will respond by increasing norepinephrine secretion, which in turn will alter cognitive function (through the prefrontal cortex), increase motivation (through

adrenal glands. Norepinephrine released from locus coeruleus will feedback to inhibit its production, and corticotropin-releasing factor will feedback to inhibit its production, while positively feeding to the locus coeruleus to increase norepinephrine production.[16]

The LC's role in cognitive function in relation to stress is complex and multi-modal. Norepinephrine released from the LC can act on α2 receptors to increase working memory, or an excess of NE may decrease working memory by binding to the lower-affinity α1 receptors.[17]

Psychiatric research has documented that enhanced noradrenergic postsynaptic responsiveness in the neuronal pathway (brain circuit) that originates in the locus coeruleus and ends in the

posttraumatic stress disorder (PTSD). The LC neurons are probably the origin of the first or second "leg" of the "PTSD circuit." An important 2005 study of deceased American army veterans from World War II has shown combat-related PTSD to be associated with a postmortem-diminished number of neurons in the locus coeruleus (LC) on the right side of the brain.[18]

In opiate withdrawal

Opioids inhibit the firing of neurons in the locus coeruleus. When opioid consumption is stopped, the increased activity of the locus coeruleus contributes to the symptoms of opiate withdrawal. The α2 adrenergic receptor agonist clonidine is used to counteract this withdrawal effect by decreasing adrenergic neurotransmission from the locus coeruleus.[19]

Rett syndrome

The genetic defect of the transcriptional regulator

locus ceruleus were shown. These Locus Coeruleus cell changes include hyperexcitability and decreased functioning of its noradrenergic innervation.[23] A reduction of the tyrosine hydroxylase (TH) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of MECP2-null male as well as in adult heterozygous female mice. Using immunoquantification techniques, a decrease of TH protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic MECP2-deficient mice.[24] However, locus coeruleus cells are not dying but are more likely losing their fully mature phenotype, since no apoptotic neurons in the pons were detected.[24] Researchers have concluded that, "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett Syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction. Restoration of normal locus ceruleus function may therefore be of potential therapeutic value in the treatment of Rett Syndrome."[23] This could explain why a norepinephrine reuptake inhibitor (desipramine, DMI), which enhances the extracellular NE levels at all noradrenergic synapses, ameliorated some Rett syndrome symptoms in a mouse model of Rett syndrome.[24]

Neurodegenerative diseases

The locus ceruleus is affected in many forms of neurodegenerative diseases: genetic and idiopathic

MRI.[29] Since the marked degeneration of locus coeruleus, and the neuroprotective properties of noradrenaline, Ian Robertson proposed the "Noradrenergic Theory of Cognitive Reserve" [30] which postulates that the upregulation of the locus coeruleus-noradrenergic system throughout the lifespan may enhance cognitive stimulation contributing to cognitive reserve preventing from neurodegeneration. Recent evidence appear to support this theory reporting the locus coeruleus integrity primarily responsible of biological brain maintenance,[31] cognitive efficiency, and reduced neuropathological burden.[31][32][33][34]

Sleep deprivation

Animal studies showed that sleep deprivation can reduce the number of neurons in the locus coeruleus. Therefore the possibility of lasting damages to human brain functions due to sleep deprivation has become a matter of discussion.[35]

History

The locus coeruleus was discovered in 1784 by

Falck-Hillarp technique, which combines freeze-dried tissue and formaldehyde to cause catecholamines (such as norepinephrine) and serotonin to fluoresce in tissue sections.[citation needed
]

Etymology

Coeruleus or caeruleus

The 'English' name locus coeruleus

noradrenergic (producing norepinephrine) nerve cell bodies.[citation needed
]

The spelling coeruleus is actually considered incorrect,

mediaeval Latin, orthographic variants such as coelum[47] for classical Latin caelum[41] and cerulans[47] for classical Latin caerulans[41] can be found. In English, the color adjective cerulean is derived from Latin caeruleus.[48] In addition, ceiling is ultimately derived from Latin caelum.[49]

Official Latin nomenclature

The official Latin nomenclature, Nomina Anatomica as ratified in Basel in 1895[50] and in Jena in 1935[51][52] contained the orthographically correct form locus caeruleus. The Nomina Anatomica published in 1955[53] inadvertently introduced the incorrect spelling locus coeruleus, without further explanation. The subsequent edition monophthongized the diphthong, resulting in locus ceruleus,[54] as they proclaimed that: "All diphthongs should be eliminated".[55] This form was retained in the subsequent edition.[55] The following two editions from 1977[56] and 1983[57] reverted the orthography back to the incorrect spelling locus coeruleus, while the subsequent edition from 1989[58] eventually returned to the correct spelling locus caeruleus. The current edition of the Nomina Anatomica, rebaptized as Terminologia Anatomica,[59] dictates locus caeruleus in its list of Latin expressions and correspondingly mentions locus caeruleus in its list of English equivalents. This is in line with the statement made by the chairman of the Terminologia Anatomica that "the committee decided that Latin terms when used in English should be in correct Latin".[60]

In popular culture

On The Big Bang Theory, season 5, episode 16 ("The Vacation Solution"), Amy tasks Sheldon with removing the locus coeruleus from a tissue sample.

See also

References

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    . Different subregions of the VTA receive glutamatergic inputs from the prefrontal cortex, orexinergic inputs from the lateral hypothalamus, cholinergic and also glutamatergic and GABAergic inputs from the laterodorsal tegmental nucleus and pedunculopontine nucleus, noradrenergic inputs from the locus ceruleus, serotonergic inputs from the raphe nuclei, and GABAergic inputs from the nucleus accumbens and ventral pallidum.
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    ISBN 9780071481274
    . The locus ceruleus (LC), which is located on the floor of the fourth ventricle in the rostral pons, contains more than 50% of all noradrenergic neurons in the brain; it innervates both the forebrain (eg, it provides virtually all the NE to the cerebral cortex) and regions of the brainstem and spinal cord. ... The other noradrenergic neurons in the brain occur in loose collections of cells in the brainstem, including the lateral tegmental regions. These neurons project largely within the brainstem and spinal cord. NE, along with 5HT, ACh, histamine, and orexin, is a critical regulator of the sleep-wake cycle and of levels of arousal. ... LC firing may also increase anxiety ...Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion ... Epinephrine occurs in only a small number of central neurons, all located in the medulla. Epinephrine is involved in visceral functions, such as control of respiration.
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A novel based upon real facts by Max Trasin, Pentian 2016

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