The locus coeruleus, which in Latin means "blue spot", is the principal site for brain synthesis ofnorepinephrine (noradrenaline). The locus coeruleus and the areas of the body affected by the norepinephrine it produces are described collectively as thelocus coeruleus-noradrenergic system orLC-NA system.[4] Norepinephrine may also be released directly into the blood from theadrenal medulla.
Micrograph showing the locus coeruleus (upper-right of image) in an axial section of thepons. Thefourth ventricle (quasi-triangular white area) is in the upper-left of the image. The midline is seen on the left. The large white area in the upper-left corner is where the cerebellum would be.HE-LFB stain.
The locus coeruleus (LC) is located in the posterior area of the rostralpons in the lateral floor of thefourth ventricle. It is composed of mostly medium-sizeneurons.Melanin granules inside the neurons contribute to its blue colour. Thus, it is also known as theblue nucleus, or thenucleus pigmentosus pontis (heavily pigmented pontine nucleus).[5] Theneuromelanin is formed by thepolymerization of norepinephrine and is analogous to the blackdopamine-based neuromelanin in thesubstantia nigra.
In adult human males,[a] the locus coeruleus has 22,000 to 51,000 total pigmented neurons that range in volume from 31,000 to 60,000 μm3.[6]
As an importanthomeostatic control center of the body, the locus coeruleus receivesafferents from the hypothalamus. Thecingulate gyrus and the amygdala also innervate the LC, allowing emotional pain and stressors to trigger noradrenergic responses. The cerebellum and afferents from theraphe nuclei also project to the LC, in particular thepontine raphe nucleus anddorsal raphe nucleus.
The projections from the locus coeruleus consist of neurons that utilize norepinephrine as their primary neurotransmitter.[7][8] These projections include the following connections:[7][8]
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:[9][10]
Research continues to reveal thatnorepinephrine (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.[19]
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 (throughnucleus accumbens), activate thehypothalamic-pituitary-adrenal axis, and increase the sympatheticdischarge/inhibit parasympathetic tone (through thebrainstem). Specific to the activation of the hypothalamic-pituitary adrenal axis, norepinephrine will stimulate the secretion ofcorticotropin-releasing factor from the hypothalamus, that inducesadrenocorticotropic hormone release from theanterior pituitary and subsequent cortisol synthesis in theadrenal 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.[20]
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.[21]
Psychiatric research has documented that enhanced noradrenergic postsynaptic responsiveness in the neuronal pathway (brain circuit) that originates in the locus coeruleus and ends in thebasolateral nuclear complex of theamygdala is a major factor in the pathophysiology of most stress-induced fear-circuitry disorders and especially inposttraumatic 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 on the right side of the brain.[22]
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. Theα2 adrenergic receptor agonistclonidine is used to counteract this withdrawal effect by decreasing adrenergic neurotransmission from the locus coeruleus.[23]
The genetic defect of the transcriptional regulatorMECP2 is responsible forRett syndrome.[24] A MECP2 deficiency has been associated to catecholaminergic dysfunctions related to autonomic and sympathoadrenergic system in mouse models of Rett Syndrome (RTT). The locus coeruleus is the major source of noradrenergic innervation in the brain and sends widespread connections to rostral (cerebral cortex, hippocampus, hypothalamus) and caudal (cerebellum, brainstem nuclei) brain areas[25] and.[26] Indeed, an alteration of this structure could contribute to several symptoms observed in MECP2-deficient mice. Changes in the electrophysiological properties of cells in thelocus ceruleus were shown. These Locus Coeruleus cell changes include hyperexcitability and decreased functioning of its noradrenergic innervation.[27] 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.[28] 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.[28] 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."[27] 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.[28]
The locus coeruleus is affected in many forms of neurodegenerative diseases: genetic and idiopathicParkinson's disease,progressive supranuclear palsy,Pick's disease, andAlzheimer's disease. It is also affected inDown syndrome.[29] For example, there is up to 80% loss of locus coeruleus neurons inAlzheimer's disease,[30] Mouse models of Alzheimer's disease show accelerated progression after chemical destruction of the locus coeruleus.[31]Neurofibrillary tangles, a primary biomarker of Alzheimer's disease, may be found in the locus coeruleus decades before any clinical symptoms.[32] The norepinephrine from locus coeruleus cells in addition to its neurotransmitter role locally diffuses from "varicosities". As such it provides an endogenousanti-inflammatory agent in the microenvironment around the neurons,glial cells, and blood vessels in the neocortex and hippocampus.[18] It has been shown that norepinephrine stimulates mouse microglia to suppressAβ-induced production ofcytokines and promotesphagocytosis of Aβ.[18] This suggests that degeneration of the locus coeruleus might be responsible for increased Aβ deposition in AD brains.[18] Degeneration of pigmented neurons in this region in Alzheimer's and Parkinson's disease can be visualized in vivo with NeuromelaninMRI.[33] Since the marked degeneration of locus coeruleus, and the neuroprotective properties of noradrenaline,Ian Robertson proposed the "Noradrenergic Theory of Cognitive Reserve"[34] which postulates that the upregulation of the locus coeruleus-noradrenergic system throughout the lifespan may enhance cognitive stimulation contributing tocognitive reserve preventing fromneurodegeneration. Evidence appear to support this theory reporting the locus coeruleus integrity primarily responsible of biological brain maintenance,[35][36][37] including brain clearance,[38] cognitive efficiency, and reduced neuropathological burden.[35][39][40][41]
Animal studies showed thatsleep 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.[42]
The locus coeruleus was discovered in 1784 byFélix Vicq-d'Azyr,[43] redescribed later byJohann Christian Reil in 1809[44] and named by the brothers Joseph and Karl Wenzel in 1812.[45][46] Highmonoamine oxidase activity in the rodent LC was found in 1959,monoamines were found in 1964 and the widespread projections of noradrenergic neurons in the 1970s.[44] An important advance in understanding the anatomical organization of the locus coeruleus was the application of theFalck-Hillarp technique, which combines freeze-dried tissue and formaldehyde to cause catecholamines (such as norepinephrine) and serotonin to fluoresce in tissue sections.[citation needed]
The 'English' namelocus coeruleus[47] is actually a Latin expression consisting of the noun,locus, "place" or "spot"[48] and the adjectivecoeruleus, "dark blue"[48] or "sky-blue".[49][50] This was aptly translated into English asblue place in 1907 in the English translation[51] of the official Latin anatomic nomenclature of 1895,Nomina Anatomica. The name of thelocus coeruleus is derived from its azure appearance in unstained brain tissue.[45] The color is due to light scattering fromneuromelanin innoradrenergic (producing norepinephrine) nerve cell bodies.[citation needed]
The spellingcoeruleus is actually considered incorrect,[52] with dictionaries of classical Latin preferringcaeruleus[48][53] instead.Caeruleus is derived fromcaelum,[53] hence the spelling with -ae, like caeluleus → caeruleus.[53]Caelum in classical Latin could refer tothe sky,the heaven orthe vault of heaven.[48] Inmediaeval Latin, orthographic variants such ascoelum[54] for classical Latincaelum[48] andcerulans[54] for classical Latincaerulans[48] can be found. In English, the color adjectivecerulean is derived from Latincaeruleus.[55] In addition,ceiling is ultimately derived from Latincaelum.[56]
The official Latin nomenclature,Nomina Anatomica as ratified inBasel in 1895[57] and inJena in 1935[58][59] contained the orthographically correct formlocus caeruleus. TheNomina Anatomica published in 1955[60] inadvertently introduced the incorrect spellinglocus coeruleus, without further explanation. The subsequent edition monophthongized thediphthong, resulting inlocus ceruleus,[61] as they proclaimed that: "All diphthongs should be eliminated".[62] This form was retained in the subsequent edition.[62] The following two editions from 1977[63]and 1983[64] reverted the orthography back to the incorrect spellinglocus coeruleus, while the subsequent edition from 1989[65] eventually returned to the correct spellinglocus caeruleus. The current edition of theNomina Anatomica, rebaptized asTerminologia Anatomica,[66] dictateslocus caeruleus in its list of Latin expressions and correspondingly mentionslocus caeruleus in its list of English equivalents. This is in line with the statement made by the chairman of theTerminologia Anatomica that "the committee decided that Latin terms when used in English should be in correct Latin".[67]
^Mouton PR, Pakkenberg B, Gundersen HJ, Price DL (August 1994). "Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals".J. Chem. Neuroanat.7 (3):185–90.doi:10.1016/0891-0618(94)90028-0.PMID7848573.S2CID25412090.
^abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 155.ISBN978-0-07-148127-4.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.
^abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 156–157.ISBN978-0-07-148127-4.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.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 157.ISBN978-0-07-148127-4.
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^Amir RE, Van, den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (October 1999). "Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2".Nat Genet.23 (2):185–8.doi:10.1038/13810.PMID10508514.S2CID3350350.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Hokfelt T, Martensson R, Bjorklund A, Kleinau S, Goldstein M. 1984. Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In Handbook of Chemical Neuroanatomy, Vol. 2. Classical Transmitters in the CNS, Part I ( A. Bjorklund and T. Hokfelt, eds.) pp. 277-379. Elsevier, New York.
^Berridge CW, Waterhouse BD (2003). "The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes".Brain Res Rev.42 (1):33–84.doi:10.1016/s0165-0173(03)00143-7.PMID12668290.S2CID477754.
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^Bondareff W, Mountjoy CQ, Roth M (February 1982). "Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia".Neurology.32 (2):164–8.doi:10.1212/wnl.32.2.164.PMID7198741.S2CID33510911.
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