Editing Locus coeruleus

{{Short description|Stress and panic response centre}}
{{Use dmy dates|date=April 2017}}
{{Infobox brain
| Name            = Locus coeruleus
| Latin           = locus caeruleus ("blue place")
| Image           = Locus-coeruleus.gif
| Caption         = Locus coeruleus and its influence pathways
| Image2          = Gray709.png
| Caption2        = [[Rhomboid fossa]]. (Locus coeruleus not labeled, but is just lateral to the [[facial colliculus]], which is labeled at center left.)
| IsPartOf        =
| Components      =
| Artery          =
| Vein            =
| Acronym         =
}}

The '''locus coeruleus''' ({{IPAc-en|s|ɪ|ˈ|ɹ|uː|l|i|ə|s}}) ('''LC'''), also spelled '''locus caeruleus''' or '''locus ceruleus''',<ref>{{Cite web|title = locus coeruleus {{!}} a bluish area of the brain stem with many norepinephrine-containing neurons|url = http://www.merriam-webster.com/dictionary/locus%2520coeruleus|website = www.merriam-webster.com|access-date = 2015-07-26}}</ref> is a [[Nucleus (neuroanatomy)|nucleus]] in the [[pons]] of the [[brainstem]] involved with [[physiology|physiological]] responses to [[stress (medicine)|stress]] and [[panic]].<ref>{{cite journal | pmid = 32954002 | pmc = 7479871 | issue = 4:2398212820930321 | title= The role of the locus coeruleus in the generation of pathological anxiety | date = July 21, 2020 | journal=Brain Neurosci. Adv. | vauthors=Morris LS, McCall JG, Charney DS, Murrough JW | volume = 4 | doi=10.1177/2398212820930321}}</ref> It is a part of the [[reticular activating system]] in the [[reticular formation]].<ref name="Khroud2022">{{cite web |last1=Khroud |first1=Navneet K. |last2=Reddy |first2=Vamsi |last3=Saadabadi |first3=Abdolreza |title=Neuroanatomy, Locus Coeruleus |url=https://www.ncbi.nlm.nih.gov/books/NBK513270/ |website=StatPearls |publisher=StatPearls Publishing |access-date=22 January 2025 |date=2025}}</ref>

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'''.<ref name=Mehler>{{cite journal
| last       = Mehler
| first      = Mark F.
| author2    = Dominick P. Purpura
| date       = March 2009
| title      = Autism, fever, epigenetics and the locus coeruleus
| journal    = [[Brain Research Reviews]]
| volume     = 59
| issue      = 2
| pages      = 388–392
| pmid       = 19059284
| pmc        = 2668953
| doi        = 10.1016/j.brainresrev.2008.11.001
}}
</ref> Norepinephrine may also be released directly into the blood from the [[adrenal medulla]].

==Anatomy==
{{multiple image
|image1 = Locus ceruleus - very low mag.jpg
|caption1 = [[Micrograph]] showing the locus coeruleus (upper-right of image) in an axial section of the [[pons]].  The [[fourth 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. [[LFB stain|HE-LFB stain]].
|image2 = Locus coeruleus highlighted.jpg
|caption2 = Locus coeruleus highlighted in green.
|}}
[[File:Locus ceruleus - high mag.jpg|thumb|[[Micrograph]] showing the locus coeruleus. [[LFB stain|HE-LFB stain]]]]

The locus coeruleus (LC) is located in the posterior area of the rostral [[pons]] in the lateral floor of the [[fourth ventricle]]. It is composed of mostly medium-size [[neurons]]. [[Melanin]] granules inside the neurons contribute to its blue colour. Thus, it is also known as the ''blue nucleus'', or the ''nucleus pigmentosus pontis'' (heavily pigmented pontine nucleus).<ref name="NIH2025">{{cite web |title=NCI Metathesaurus |url=https://ncim.nci.nih.gov/ncimbrowser/pages/concept_details.jsf?code=C0023951&type=all&sortBy2=cui&sortBy=name&sab=MSH |website=ncim.nci.nih.gov |access-date=23 January 2025}}</ref> 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 μm<sup>3</sup>.<ref>{{cite journal | pmid = 7848573 | volume=7 | issue=3 | title=Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals |date=August 1994 | journal=J. Chem. Neuroanat. | pages=185–90 |vauthors=Mouton PR, Pakkenberg B, Gundersen HJ, Price DL | doi=10.1016/0891-0618(94)90028-0| s2cid=25412090 }}</ref>

==Connections==
The projections of this nucleus reach far and wide. For example, they innervate the [[spinal cord]], the brain stem, [[cerebellum]], [[hypothalamus]], the [[hippocampus]], [[thalamus|the thalamic relay nuclei]], the [[amygdala]], the basal [[telencephalon]], and the [[Cerebral cortex|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 [[homeostasis|homeostatic]] control center of the body, the locus coeruleus receives [[afferent nerve fiber|afferents]] from the hypothalamus. The [[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:
*The [[medial (anatomy)|Medial]] [[prefrontal cortex]], whose connection is constant, excitatory, and increases in strength with raised activity levels in the subject
*The [[Nucleus paragigantocellularis]], which integrates [[Autonomic nervous system|autonomic]] and [[natural environment|environment]]al stimuli
*The [[Nucleus prepositus]], which is involved in gaze
*The Lateral hypothalamus, which releases [[orexin]], which, as well as its other functions, is excitatory in the locus coeruleus.

===Outputs===
The projections from the locus coeruleus consist of neurons that utilize norepinephrine as their primary neurotransmitter.<ref name="VTA inputs" /><ref name="Noradrenergic pathways" /> These projections include the following connections:<ref name="VTA inputs">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 155 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote= 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.}}</ref><ref name="Noradrenergic pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 156–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=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.&nbsp;... 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.&nbsp;... LC firing may also increase anxiety&nbsp;...Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion&nbsp;... 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.<!--Note: the noradrenergic pathways are based upon a projection diagram that can't be quoted.-->}}</ref>
:* LC → [[Amygdala]] and [[Hippocampus]]
:* LC → [[Brain stem]] and [[Spinal cord]]
:* LC → [[Cerebellum]]
:* LC → [[Cerebral cortex]]
:* LC → [[Hypothalamus]]
:* LC → [[Tectum]]
:* LC → [[Thalamus]]
:* LC → [[Ventral tegmental area]]

==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:<ref name="pmid19917994">{{cite journal | author = Benarroch EE | title = The locus ceruleus norepinephrine system: functional organization and potential clinical significance | journal = Neurology | volume = 73 | issue = 20 | pages = 1699–704 |date=November 2009  | pmid = 19917994 | doi = 10.1212/WNL.0b013e3181c2937c | s2cid = 28805417 }}</ref><ref name="Malenka pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin}}</ref>
* [[Arousal]] and [[sleep-wake cycle]]
* [[Attention]]<ref>{{Cite journal|last1=Bouret|first1=Sebastien|last2=Sara|first2=Susan J.|date=2005|title=Network reset: a simplified overarching theory of locus coeruleus noradrenaline function|url=http://dx.doi.org/10.1016/j.tins.2005.09.002|journal=Trends in Neurosciences|volume=28|issue=11|pages=574–582|doi=10.1016/j.tins.2005.09.002|pmid=16165227|s2cid=205403074|issn=0166-2236|url-access=subscription}}</ref> and [[memory]]
* Behavioral and [[cognitive flexibility]],<ref>{{Cite journal|last1=Beversdorf|first1=D Q.|last2=Hughes|first2=J D.|last3=Steinberg|first3=B A.|last4=Lewis|first4=L D.|last5=Heilman|first5=K M.|date=1999|title=Noradrenergic modulation of cognitive flexibility in problem solving|url=https://dx.doi.org/10.1097%2F00001756-199909090-00012|journal=NeuroReport|language=en|volume=10|issue=13|pages=2763–2767|doi=10.1097/00001756-199909090-00012|pmid=10511436|issn=0959-4965|url-access=subscription}}</ref> [[creativity]],<ref>{{Cite journal|last1=Lin|first1=Hause|last2=Vartanian|first2=Oshin|date=2018|title=A Neuroeconomic Framework for Creative Cognition|url=http://journals.sagepub.com/doi/10.1177/1745691618794945|journal=Perspectives on Psychological Science|language=en|volume=13|issue=6|pages=655–677|doi=10.1177/1745691618794945|pmid=30304640|s2cid=206778956|issn=1745-6916}}</ref> behavioral inhibition and [[stress (psychological)]]
* [[Cognitive control]]
* [[Decision-making|Decision making]] and utility maximization<ref>{{Cite journal|last1=Aston-Jones|first1=Gary|last2=Cohen|first2=Jonathan D.|date=2005-07-21|title=An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance|url=http://dx.doi.org/10.1146/annurev.neuro.28.061604.135709|journal=Annual Review of Neuroscience|volume=28|issue=1|pages=403–450|doi=10.1146/annurev.neuro.28.061604.135709|pmid=16022602|s2cid=535645 |issn=0147-006X|url-access=subscription}}</ref>
* [[Emotions]]
* [[Neuroplasticity]]
* Posture and [[balance (ability)|balance]]
* Global model failure where predictions about the world are strongly violated<ref name="c485">{{cite journal |last=Jordan |first=Rebecca |date=2024 |title=The locus coeruleus as a global model failure system |journal=Trends in Neurosciences |volume=47 |issue=2 |pages=92–105 |doi=10.1016/j.tins.2023.11.006|doi-access=free |pmid=38102059 }}</ref>
The locus coeruleus is a part of the [[reticular activating system]], and is almost completely inactivated in [[rapid eye movement sleep]].<ref name="Schwartz 2008">{{cite journal|last=Schwartz|first=JR|author2=Roth, T |title=Neurophysiology of sleep and wakefulness: basic science and clinical implications.|journal=Current Neuropharmacology|date=December 2008|volume=6|issue=4|pages=367–78|pmid=19587857|doi=10.2174/157015908787386050|pmc=2701283}}</ref>

==Pathophysiology==
The locus coeruleus may figure in [[clinical depression]], [[panic disorder]], [[Parkinson's disease]], [[Alzheimer's disease]]<ref name="Heneka2010" /> and [[anxiety]]. Some medications including [[norepinephrine reuptake inhibitor]]s ([[reboxetine]], [[atomoxetine]]), [[serotonin-norepinephrine reuptake inhibitor]]s ([[venlafaxine]], [[duloxetine]]), and [[norepinephrine-dopamine reuptake inhibitor]]s ([[bupropion]]) are believed to show efficacy by acting upon [[neuron]]s 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.<ref>Ressler KJ, Nemeroff CB. Role of norepinephrine in the pathophysiology of neuropsychiatric disorders. CNS Spectr. 2001 Aug;6(8):663-6, 670.</ref>

===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 [[nucleus accumbens]]), activate the [[hypothalamic-pituitary-adrenal axis]], and increase the sympathetic [[membrane potential|discharge]]/inhibit parasympathetic tone (through the [[brainstem]]). Specific to the activation of the hypothalamic-pituitary adrenal axis, norepinephrine will stimulate the secretion of [[corticotropin-releasing factor]] from the hypothalamus, that induces [[adrenocorticotropic hormone]] release from the [[anterior pituitary]] and subsequent cortisol synthesis in the [[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.<ref name="Benarroch">{{cite journal | author = Benarroch EE | date = November 2009 | title = The locus coeruleus norepinephrine system: functional organization and potential clinical significance | journal = Neurology | volume = 73 | issue = 20| pages = 1699–704 | doi=10.1212/wnl.0b013e3181c2937c | pmid=19917994| s2cid = 28805417 }}</ref>

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.<ref name="Ramos">{{cite journal |vauthors=Ramos BP, Arnsten AF | year = 2007 | title = Adrenergic pharmacology and cognition: focus on the prefrontal cortex | journal = Pharmacol Ther | volume = 113 | issue = 3| pages = 523–536 | doi=10.1016/j.pharmthera.2006.11.006 | pmid=17303246 | pmc=2151919}}</ref>

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 [[basolateral nuclear complex]] of the [[amygdala]] is a major factor in the pathophysiology of most stress-induced fear-circuitry disorders and especially in [[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 on the right side of the brain.<ref>{{cite journal |vauthors=Bracha HS, Garcia-Rill E, Mrak RE, Skinner R |title=Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD |journal=The Journal of Neuropsychiatry and Clinical Neurosciences |volume=17 |issue=4 |pages=503–9 |year=2005 |pmid=16387990 |doi=10.1176/appi.neuropsych.17.4.503|pmc=4484762 }}</ref>

===In opiate withdrawal===
[[Opioid]]s 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 [[Alpha-2 adrenergic receptor|α<sub>2</sub> adrenergic receptor]] agonist [[clonidine]] is used to counteract this withdrawal effect by decreasing adrenergic neurotransmission from the locus coeruleus.<ref>{{cite journal |author1=Devenyi P. |author2=Mitwalli A. |author3=Graham W. | date = November 1982 | title = Clonidine therapy for narcotic withdrawal | journal = Can Med Assoc J | volume = 127 | issue = 10| pages = 1009–1011 | pmc=1862300 | pmid=7139433 }}</ref>

===Rett syndrome ===
The genetic defect of the transcriptional regulator [[MECP2]] is responsible for [[Rett syndrome]].<ref name="Amir">{{cite journal | author = Amir RE, Van, den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY | date = October 1999 | title = Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 | doi = 10.1038/13810 | pmid = 10508514 | journal = Nat Genet | volume = 23 | issue = 2| pages = 185–8 | s2cid = 3350350 }}</ref> 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<ref name="Hokfelt">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.</ref> and.<ref name="Berridge">{{cite journal |vauthors=Berridge CW, Waterhouse BD | year = 2003 | title = The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes | journal = Brain Res Rev | volume = 42 | issue = 1| pages = 33–84 | doi=10.1016/s0165-0173(03)00143-7 | pmid=12668290| s2cid = 477754 }}</ref> Indeed, an alteration of this structure could contribute to several symptoms observed in MECP2-deficient mice. Changes in the electrophysiological properties of cells in the [[locus ceruleus]] were shown. These Locus Coeruleus cell changes include hyperexcitability and decreased functioning of its noradrenergic innervation.<ref name="Taneja">{{cite journal |vauthors=Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB | year = 2009 | title = Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome | journal = Journal of Neuroscience | volume = 29 | issue = 39| pages = 12187–12195 | doi = 10.1523/JNEUROSCI.3156-09.2009 | pmid=19793977 | pmc=2846656}}</ref> 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.<ref name="Roux">{{cite journal |vauthors=Roux JC, Panayotis N, Dura E, Villard L | year = 2009 | title = Progressive Noradrenergic Deficits in the Locus Coeruleus of MECP2 Deficient Mice | url = http://www3.interscience.wiley.com/cgi-bin/fulltext/123208150/HTMLSTART | archive-url = https://archive.today/20121218023802/http://www3.interscience.wiley.com/cgi-bin/fulltext/123208150/HTMLSTART | url-status = dead | archive-date = 2012-12-18 | journal = J Neurosci Res | volume =  88| issue = 7| pages = 1500–9 | doi = 10.1002/jnr.22312 | pmid = 19998492 | s2cid = 3404695 | url-access = subscription }}</ref> 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.<ref name="Roux"/> 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."<ref name="Taneja"/> 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.<ref name="Roux"/>

===Neurodegenerative diseases===
The locus coeruleus is affected in many forms of neurodegenerative diseases: genetic and idiopathic [[Parkinson's disease]], [[progressive supranuclear palsy]], [[Pick's disease]], and [[Alzheimer's disease]]. It is also affected in [[Down syndrome]].<ref name=" Esiri">Esiri MM. et al. (2004). Neuropathology of dementia. 2nd ed. Cambridge University Press.</ref> For example, there is up to 80% loss of locus coeruleus neurons in [[Alzheimer's disease]],<ref name="Bondaref">{{cite journal |vauthors=Bondareff W, Mountjoy CQ, Roth M | date = February 1982 | title = Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia | journal = Neurology | volume = 32 | issue = 2| pages = 164–8 | doi=10.1212/wnl.32.2.164| pmid = 7198741 | s2cid = 33510911 }}</ref> Mouse models of Alzheimer's disease show accelerated progression after chemical destruction of the locus coeruleus.<ref name="Heneka">{{cite journal |vauthors=Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss WD, Klockgether T, Staufenbiel M | date = February 2006 | title = Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice | journal = J Neurosci | volume = 26 | issue = 5| pages = 1343–54 | doi=10.1523/jneurosci.4236-05.2006 | pmid=16452658| pmc = 6675491 }}</ref> [[Neurofibrillary tangle]]s, a primary biomarker of Alzheimer's disease, may be found in the locus coeruleus decades before any clinical symptoms.<ref>{{cite news |title=The Brain's "Blue Spot" may Help Identify Alzheimer's Earlier |first=Ruairi J |last=Mackenzie |url=https://www.technologynetworks.com/neuroscience/news/the-brains-blue-spot-may-help-identify-alzheimers-earlier-353919 |publisher=Technology Networks |date=September 22, 2021 |access-date=September 30, 2021}}</ref> The norepinephrine from locus coeruleus cells in addition to its neurotransmitter role locally diffuses from "varicosities". As such it provides an endogenous [[anti-inflammatory]] agent in the microenvironment around the neurons, [[glial cell]]s, and blood vessels in the neocortex and hippocampus.<ref name="Heneka2010">{{cite journal |vauthors=Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP | year = 2010 | title = Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine | journal = Proc Natl Acad Sci U S A | volume = 107 | issue = 13| pages = 6058–6063 | doi = 10.1073/pnas.0909586107 | pmid = 20231476 | pmc=2851853| bibcode = 2010PNAS..107.6058H | doi-access = free }}</ref> It has been shown that norepinephrine stimulates mouse microglia to suppress [[Aβ]]-induced production of [[cytokine]]s and promotes [[phagocytosis]] of Aβ.<ref name="Heneka2010"/> This suggests that degeneration of the locus coeruleus might be responsible for increased Aβ deposition in AD brains.<ref name="Heneka2010"/> Degeneration of pigmented neurons in this region in Alzheimer's and Parkinson's disease can be visualized in vivo with Neuromelanin [[MRI]].<ref>{{cite journal |vauthors=Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, Takahashi S, Ehara S, Terayama Y, Sakai A | title = Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease | journal = NeuroReport | volume = 17 | issue = 11 | pages = 1215–8 | date = July 2006 | pmid = 16837857 | doi=10.1097/01.wnr.0000227984.84927.a7| s2cid = 24597825 }}</ref> Since the marked degeneration of locus coeruleus, and the neuroprotective properties of noradrenaline, [[Ian Robertson (psychologist)|Ian Robertson]] proposed the "''Noradrenergic Theory of Cognitive Reserve''" <ref>{{Cite journal |last=Robertson |first=Ian H. |date=January 2013 |title=A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease |url=https://pubmed.ncbi.nlm.nih.gov/22743090/ |journal=Neurobiology of Aging |volume=34 |issue=1 |pages=298–308 |doi=10.1016/j.neurobiolaging.2012.05.019 |issn=1558-1497 |pmid=22743090|hdl=2262/66944 |s2cid=207159981 |hdl-access=free }}</ref>  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. Evidence appear to support this theory reporting the locus coeruleus integrity primarily responsible of biological brain maintenance,<ref name=":0">{{Cite journal |last1=Plini |first1=Emanuele R. G. |last2=O'Hanlon |first2=Erik |last3=Boyle |first3=Rory |last4=Sibilia |first4=Francesca |last5=Rikhye |first5=Gaia |last6=Kenney |first6=Joanne |last7=Whelan |first7=Robert |last8=Melnychuk |first8=Michael C. |last9=Robertson |first9=Ian H. |last10=Dockree |first10=Paul M. |date=2021-07-20 |title=Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer's Disease Neuroimaging Initiative |journal=Cells |volume=10 |issue=7 |pages=1829 |doi=10.3390/cells10071829 |issn=2073-4409 |pmc=8306442 |pmid=34359997|doi-access=free }}</ref> including brain clearance,<ref>{{Cite journal |last=Hauglund |first=Natalie L. |last2=Andersen |first2=Mie |last3=Tokarska |first3=Klaudia |last4=Radovanovic |first4=Tessa |last5=Kjaerby |first5=Celia |last6=Sørensen |first6=Frederikke L. |last7=Bojarowska |first7=Zuzanna |last8=Untiet |first8=Verena |last9=Ballestero |first9=Sheyla B. |last10=Kolmos |first10=Mie G. |last11=Weikop |first11=Pia |last12=Hirase |first12=Hajime |last13=Nedergaard |first13=Maiken |date=2025-02-06 |title=Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep |url=https://www.cell.com/cell/abstract/S0092-8674(24)01343-6 |journal=Cell |language=English |volume=188 |issue=3 |pages=606–622.e17 |doi=10.1016/j.cell.2024.11.027 |issn=0092-8674 |pmid=39788123|url-access=subscription }}</ref> cognitive efficiency, and reduced neuropathological burden.<ref name=":0" /><ref>{{Cite journal |last1=Clewett |first1=David V. |last2=Lee |first2=Tae-Ho |last3=Greening |first3=Steven |last4=Ponzio |first4=Allison |last5=Margalit |first5=Eshed |last6=Mather |first6=Mara |date=January 2016 |title=Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging |journal=Neurobiology of Aging |volume=37 |pages=117–126 |doi=10.1016/j.neurobiolaging.2015.09.019 |issn=1558-1497 |pmc=5134892 |pmid=26521135}}</ref><ref>{{Cite journal |last1=Dutt |first1=Shubir |last2=Li |first2=Yanrong |last3=Mather |first3=Mara |last4=Nation |first4=Daniel A. |last5=Alzheimer's Disease Neuroimaging Initiative |date=2020 |title=Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease |journal=Journal of Alzheimer's Disease  |volume=77 |issue=4 |pages=1579–1594 |doi=10.3233/JAD-200187 |issn=1875-8908 |pmc=7868064 |pmid=32925030}}</ref><ref>{{Cite journal |last1=Dahl |first1=Martin J. |last2=Mather |first2=Mara |last3=Werkle-Bergner |first3=Markus |last4=Kennedy |first4=Briana L. |last5=Guzman |first5=Samuel |last6=Hurth |first6=Kyle |last7=Miller |first7=Carol A. |last8=Qiao |first8=Yuchuan |last9=Shi |first9=Yonggang |last10=Chui |first10=Helena C. |last11=Ringman |first11=John M. |date=April 2022 |title=Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer's disease |journal=Neurobiology of Aging |volume=112 |pages=39–54 |doi=10.1016/j.neurobiolaging.2021.11.006 |issn=1558-1497 |pmc=8976827 |pmid=35045380}}</ref>

=== 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.<ref name="pmid35691776">{{cite journal| author=Zamore Z, Veasey SC| title=Neural consequences of chronic sleep disruption. | journal=Trends Neurosci | year= 2022 | volume= 45 | issue= 9 | pages= 678–691 | pmid=35691776 | doi=10.1016/j.tins.2022.05.007 | pmc=9388586 }}</ref>

==History==
The locus coeruleus was discovered in 1784 by [[Félix Vicq-d'Azyr]],<ref name=" Tubbs11">{{cite journal | pmid = 21445631| volume=27 | issue=7 | title=Félix Vicq d'Azyr (1746-1794): early founder of neuroanatomy and royal French physician |date=July 2011 | journal=Childs Nerv Syst | pages=1031–4 |vauthors=Tubbs RS, Loukas M, Shoja MM, Mortazavi MM, Cohen-Gadol AA | doi=10.1007/s00381-011-1424-y | doi-access=free }}</ref> redescribed later by [[Johann Christian Reil]] in 1809<ref name=" Maeda00">{{cite journal | pmid = 10708919 | volume=18 | issue=1–2 | title=The locus coeruleus: history |date=February 2000 | journal=J. Chem. Neuroanat. | pages=57–64 | author=Maeda T| doi=10.1016/s0891-0618(99)00051-4 | s2cid=26486778 }}</ref> and named by the brothers Joseph and Karl Wenzel in 1812.<ref name=" Wenzel">{{cite book |last1=Wenzel |first1=Josephus |last2=Wenzel |first2=Carolus |title=De penitiori structura cerebri hominis et brutorum |date=1812 |publisher=Cottam |location=Tübingen |page=[https://archive.org/details/BIUSante_01631/page/n192 168] |url=https://archive.org/details/BIUSante_01631 |access-date=26 July 2019 |language=la}}</ref><ref>Swanson, LW. Neuroanatomical terminology : a lexicon of classical origins and historical foundations. Oxford University Press, 2014. England {{ISBN|9780195340624}}</ref> High [[monoamine 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.<ref name=" Maeda00" /> An important advance in understanding the anatomical organization of the locus coeruleus was the application of the [[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|date=April 2014}}

===Etymology===
====''Coeruleus or caeruleus''====
The 'English' name ''locus coeruleus''<ref name="Dorland">Anderson, D.M. (2000). ''Dorland's illustrated medical dictionary'' (29th edition). Philadelphia/London/Toronto/Montreal/Sydney/Tokyo: W.B. Saunders Company.</ref> is actually a Latin expression consisting of the noun, ''locus'', "place" or "spot"<ref name="Lewis & Short">Lewis, C.T. & Short, C. (1879). ''A Latin dictionary founded on Andrews' edition of Freund's Latin dictionary.'' Oxford: Clarendon Press.</ref> and the adjective ''coeruleus'', "dark blue"<ref name="Lewis & Short"/> or "sky-blue".<ref name="Kraus">Kraus, L.A. (1844). ''Kritisch-etymologisches medicinisches Lexikon'' (Dritte Auflage). Göttingen: Verlag der Deuerlich- und Dieterichschen Buchhandlung.</ref><ref name="Foster1891">Foster, F.D. (1891-1893). ''An illustrated medical dictionary. Being a dictionary of the technical terms used by writers on medicine and the collateral sciences, in the Latin, English, French, and German languages.'' New York: D. Appleton and Company.</ref> This was aptly translated into English as ''blue place'' in 1907 in the English translation<ref name="Barker1907">Barker, L.W. (1907). ''Anatomical terminology with special reference to the [BNA]. With vocabularies in Latin and English and illustrations.'' Philadelphia: P. Blakiston's Son & Co.</ref> of the official Latin anatomic nomenclature of 1895, ''[[Nomina Anatomica]]''. The name of the ''locus coeruleus'' is derived from its azure appearance in unstained brain tissue.<ref name=" Wenzel" /> The color is due to light scattering from [[neuromelanin]] in [[noradrenergic]] (producing norepinephrine) nerve cell bodies.{{citation needed|date=April 2014}}

The spelling ''coeruleus'' is actually considered incorrect,<ref name="Triepel1910b">Triepel, H. (1910). ''Die anatomischen Namen. Ihre Ableitung und Aussprache. Mit einem Anhang: Biographische Notizen.''(Dritte Auflage). Wiesbaden: Verlag J.F. Bergmann.</ref> with dictionaries of classical Latin preferring ''caeruleus''<ref name="Lewis & Short"/><ref name="Wageningen1921">Wageningen, J. van & Muller, F. (1921). ''Latijnsch woordenboek.'' (3de druk). 
Groningen/Den Haag: J.B. Wolters' Uitgevers-Maatschappij</ref> instead. ''Caeruleus'' is derived from ''caelum'',<ref name="Wageningen1921"/> hence the spelling with -ae, like caeluleus → caeruleus.<ref name="Wageningen1921"/> ''Caelum'' in classical Latin could refer to ''the sky'', ''the heaven'' or ''the vault of heaven''.<ref name="Lewis & Short"/> In [[mediaeval Latin]], orthographic variants such as ''coelum''<ref name="Niermeyer1976">Niermeyer, J.F. (1976). ''Mediae Latinitatis lexicon minus.Lexique Latin médiéval-Français/Anglais. A medieval Latin-French/English dictionary.'' Leiden: E.J. BriLL.</ref> for classical Latin ''caelum''<ref name="Lewis & Short"/> and ''cerulans''<ref name="Niermeyer1976"/> for classical Latin ''caerulans''<ref name="Lewis & Short"/> can be found. In English, the color adjective ''cerulean'' is derived from Latin ''caeruleus''.<ref name="Donald1880">Donald, J. (1880). ''Chambers's etymological dictionary of the English language.'' London/Edinburgh: W. & R. Chambers.</ref> In addition, ''[[ceiling]]'' is ultimately derived from Latin ''caelum''.<ref name="Klein1971">Klein, E. (1971). A comprehensive etymological dictionary of the English language. Dealing with the origin of words and their sense development thus illustration the history of civilization and culture. Amsterdam: Elsevier Science B.V.</ref>

====''Official Latin nomenclature''====
The official Latin nomenclature, ''[[Nomina Anatomica]]'' as ratified in [[Basel]] in 1895<ref name="His">His, W. (1895). ''Die anatomische Nomenclatur. Nomina Anatomica. Der von der Anatomischen Gesellschaft auf ihrer IX. Versammlung in Basel angenommenen Namen''. Leipzig: Verlag Veit & Comp.</ref> and in [[Jena]] in 1935<ref name="Kopsch">Kopsch, F. (1941). ''Die Nomina anatomica des Jahres 1895 (B.N.A.) nach der Buchstabenreihe geordnet und gegenübergestellt den Nomina anatomica des Jahres 1935 (I.N.A.)'' (3. Auflage). Leipzig: Georg Thieme Verlag.</ref><ref name="Stieve1949">Stieve, H. (1949). ''Nomina Anatomica. Zusammengestellt von der im Jahre 1923 gewählten Nomenklatur-Kommission, unter Berücksichtigung der Vorschläge der Mitglieder der Anatomischen Gesellschaft, der Anatomical Society of Great Britain and Ireland, sowie der American Association of Anatomists, überprüft und durch Beschluß der Anatomischen Gesellschaft auf der Tagung in Jena 1935 endgúltig angenommen.'' (4th edition). Jena: Verlag Gustav Fischer.</ref> contained the orthographically correct form ''locus caeruleus''. The ''Nomina Anatomica'' published in 1955<ref name="NA1">International Anatomical Nomenclature Committee (1955). ''Nomina Anatomica'' . London/Colchester:Spottiswoode, Ballantyne and Co. Ltd.</ref> inadvertently introduced the incorrect spelling ''locus coeruleus'', without further explanation. The subsequent edition monophthongized the [[diphthong]], resulting in ''locus ceruleus'',<ref name="Donáth1969">Donáth, T. & Crawford, G.C.N. (1969). ''Anatomical dictionary with nomenclature and explanatory notes.'' Oxford/London/Edinburgh/New York/Toronto/Sydney/Paris/Braunschweig: Pergamon Press.</ref> as they proclaimed that: "All diphthongs should be eliminated".<ref name="NA3">International Anatomical Nomenclature Committee (1966). ''Nomina Anatomica''. Amsterdam: Excerpta Medica Foundation.</ref> This form was retained in the subsequent edition.<ref name="NA3"/> The following two editions from 1977<ref name="NA4">International Anatomical Nomenclature Committee (1977). ''Nomina Anatomica, together with Nomina Histologica and Nomina Embryologica''. Amsterdam-Oxford: Excerpta Medica.</ref>
and 1983<ref name="NA5">International Anatomical Nomenclature Committee (1983). ''Nomina Anatomica, together with Nomina Histologica and Nomina Embryologica''. Baltimore/London: Williams & Wilkins</ref> reverted the orthography back to the incorrect spelling ''locus coeruleus'', while the subsequent edition from 1989<ref name="NA6">International Anatomical Nomenclature Committee (1989). ''Nomina Anatomica, together with Nomina Histologica and Nomina Embryologica''. Edinburgh: Churchill Livingstone.</ref> eventually returned to the correct spelling ''locus caeruleus''. The current edition of the ''Nomina Anatomica'', rebaptized as ''[[Terminologia Anatomica]]'',<ref name="FCAT">Federative Committee on Anatomical Terminology (FCAT) (1998). ''Terminologia Anatomica''. Stuttgart: Thieme</ref> 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".<ref name="Whitmore2009">{{cite journal | last1 = Whitmore | first1 = I. | year = 2009 | title = Terminologia Anatomica includes terms in English for all scientists writing in English | journal = Anatomical Sciences Education | volume = 2 | issue = 3| page = 141 |pmid = 19496164 | doi = 10.1002/ase.88 | s2cid = 11631156 }}</ref>

== 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.

In Season 3, Episode 14 of Fear The Walking Dead, a man offers preserved Locus Coeruleus as drugs.

==References==
{{Reflist|30em}}

==External links==
{{Commons category|Locus coeruleus}}
*[http://faculty.etsu.edu/currie/ras.htm "A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness"] at [[East Tennessee State University]]
*[https://pubmed.ncbi.nlm.nih.gov/38336865/ Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease]
* {{BrainMaps|locus%20coeruleus|locus coeruleus}}
* [https://web.archive.org/web/20061105183531/http://homepage.psy.utexas.edu/homepage/class/Psy301/Salinas/sec2/Brain/31.GIF Diagram] at [[University of Texas at Austin]]
* [http://www.healthsystem.virginia.edu/internet/pediatrics/hcp/adhdbrainanatomy.cfm Diagram] {{Webarchive|url=https://archive.today/20121212174217/http://www.healthsystem.virginia.edu/internet/pediatrics/hcp/adhdbrainanatomy.cfm |date=12 December 2012 }} at [[University of Virginia]]
* https://web.archive.org/web/20070512234228/http://www2.umdnj.edu/~neuro/studyaid/Practical2000/Q45.htm

{{Pons}}
{{Fourth ventricle}}
{{Neurotransmitter systems}}

{{Authority control}}

{{DEFAULTSORT:Locus Coeruleus}}
[[Category:Pons]]
[[Category:Norepinephrine]]