Saturday, July 16, 2016

The importance of functions of Locus Coeruleus

Brain region that processes sensory signals from all areas of the body.  (posted on

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The locus coeruleus  is a nucleus in the pons (part of the brainstem) involved with physiological responses to stress and panic.  (brain stem - The portion of the brain, consisting of the medulla oblongata, pons Varolii, and midbrain, that connects the spinal cord to the forebrain and cerebrum.  - posted at

The medulla oblongata is the lower half of the brainstem. It is often referred to simply as the medulla. The medulla contains thecardiacrespiratoryvomiting and vasomotor centers and deals with autonomic, (involuntary) functions, such as breathingheart rateand blood pressure.
The bulb is an archaic term for the medulla oblongata; in modern clinical usage, it sometimes includes the pons as well. The wordbulbar therefore refers to the nerves and tracts connected to the medulla, and also by association to the muscles thus innervated, those of the tongue, pharynx and larynx.  

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The locus coeruleus 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.  (The adrenal medulla (suprarenal medulla) is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine (adrenaline),norepinephrine (noradrenaline), and a small amount of dopamine in response to stimulation by sympathetic preganglionic neurons.)

The name is derived from the Latin words coeruleus and locus, meaning the dark blue spot, a name derived from its azure appearance in unstained brain tissue. The color is due to light scattering from melanin in noradrenergic (producing or activated by norepinephrine) nerve cell bodies. The phenomenon is magnified by the Falck-Hillarp technique°, which combines freeze-dried tissue and formaldehyde to fluoresce the catecholamines and serotonin contained in the tissue.Caeruleus is the classical Latin spelling, but coeruleus is the more common spelling. The spelling ceruleus is an American English form. The etymology is probably from " caelum" meaning "sky" [whence ceiling].

The locus coeruleus (or "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 of the LC contribute to its blue color. 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 noradrenaline 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]
The projections of this nucleus reach far and wide. For example, they innervate the spinal cord, the brain stem, cerebellum,hypothalamusthe thalamic relay nuclei, the amygdala, the basal 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 homeostatic control center of the body, the locus coeruleus receives 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 nucleus raphes pontis and nucleus raphes dorsalis.
The locus coeruleus receives inputs from a number of other brain regions, primarily:
·         Medial prefrontal cortex, whose connection is constant, excitatory, and increases in strength with raised activity levels in the subject
·         Nucleus paragigantocellularis, which integrates autonomic and environmental stimuli
·         Nucleus praepositus hypoglossi, which is involved in gaze
·         Lateral hypothalamus, which releases orexin, which, as well as its other functions, is excitatory in the locus coeruleus.

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:[5]
·         Neuroplasticity
·         Arousal and sleep-wake cycle
·         Attention and memory
·         Emotions
·         Behavioral flexibility, behavioral inhibition and stress (psychological)
·         Posture and balance
The locus coeruleus may figure in clinical depressionpanic disorderParkinson's disease, and anxiety. Some medications including norepinephrine reuptake inhibitors (reboxetine,atomoxetine), serotonin-norepinephrine reuptake inhibitors (venlafaxineduloxetine), and norepinephrine-dopamine reuptake inhibitors (bupropion) are believed to show efficacy by acting upon neurons in this area.

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 discharge/inhibit parasympathetic tone (through the brainstem). Specific to the activation of the hypothalamo-pituitary adrenal axis, norepinephrine will stimulate the secretion of corticotropin-releasing factor from the hypothalamus, which 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 hormone will feedback to inhibit its production, while positively feeding to the locus coeruleus to increase norepinephrine production.[5]
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.[6]
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 nucleus of the amygdala is a major factor in the pathophysiology of most stress-induced fear-circuitry disorders and especially in posttraumatic stress disorder (PTSD)[7]
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 alpha2 adrenoceptor agonist clonidine is used to counteract this withdrawal effect by decreasing adrenergic neurotransmission from the locus coeruleus.[8]
Rett syndrome
The genetic defect of the transcriptional regulator MECP2 is responsible for Rett syndrome.[9] 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[10] and.[11] 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.[12] It is interesting to note that 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.[13] 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.[13] 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 ceruleus 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."[12] 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.[13]
Neurodegenerative diseases[edit]
The locus ceruleus is affected in many forms of neurodegenerative diseases: genetic and idiopathic Parkinson's diseaseprogressive supranuclear palsyPick's disease orAlzheimer's disease. It is also affected in Down syndrome.[14] For example there is up to 70% loss of locus ceruleus neurons in Alzheimer's disease.[15] Mouse models of Alzheimer's disease show accelerated progression after chemical destruction of the locus ceruleus [16] The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses from "varicosities". As such it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[17] It has been shown that norepinephrine stimulates mouse microglia to suppress -induced production of cytokines and theirphagocytosis of Aβ.[17] This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.[17]
See also[edit]
·         Raphe nucleus
·         Substantia nigra
·         Reticular formation
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2.       Jump up^ Maeda T (February 2000). "The locus coeruleus: history". J. Chem. Neuroanat. 18 (1-2): 57–64. PMID 10708919

3.       Jump up^ Mehler, Mark F.; Dominick P. Purpura (March 2009). "Autism, fever, epigenetics and the locus coeruleus"

. Retrieved 9 June 2011.
4.       Jump up^ 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

5.       Jump up to:a b Benarroch EE. The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology. 2009 Nov 17;73(20):1699-704.
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8.       Jump up^ P. Devenyi, A. Mitwalli, and W. Graham Clonidine therapy for narcotic withdrawal. Can Med Assoc 1982 November 15; 127(10): 1009–1011.

9.       Jump up^ Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Nat Genet. 1999 Oct 23(2):185-8
10.   Jump up^ 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.
11.   Jump up^ Berridge CW,Waterhouse BD 2003 The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42: 33-84
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13.   Jump up to:a b c Roux JC, Panayotis N, Dura E, Villard L. (2009) Progressive Noradrenergic Deficits in the Locus Coeruleus of MECP2 Deficient Mice J Neurosci Res

14.   Jump up^ Esiri MM. et al. (2004). Neuropathology of dementia. 2nd ed. Cambridge University Press.
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16.   Jump up^ 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. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54.
17.   Jump up to:a b c 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. (2010).Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine.

 Proc Natl Acad Sci U S A. 107:6058–6063doi:10.1073/pnas.0909586107

External links

·         Diagram

·         Diagram

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Shown is a sagittal section of the brainstem modeling some important elements of the circuit regulating muscle tone. Circled region shows the inputs and outputs to the locus coeruleus, which contains noradrenergic cells. The locus coeruleus projects ascending axons to the forebrain, where it can increase alertness, and to spinal motoneurons, where it facilitates muscle tone. Locus coeruleus cells shut off before and during REM sleep and before and during cataplexy. Muscle tone is lost in REM sleep. It is also lost in cataplexy, but in cataplexy waking is maintained. The cessation of noradrenaline release disfacilitates muscle tone. Carter et al.2 found that depletion of noradrenaline by high-frequency stimulation also produces a loss of muscle tone. Hypocretin (orexin) neurons, located in the hypothalamus and inactive in sleep, excite both locus coeruleus and motoneurons. Loss of muscle tone in REM sleep and cataplexy results not only from disfacilitation but also from active inhibition by glycine and GABA. The glutamatergic cells in the pontine inhibitory region, which are selectively active in REM sleep, inhibit locus coeruleus neurons through a GABAergic interneuron and excite cells in the medullary inhibitory region, which directly or indirectly release GABA and glycine onto motoneurons, depicted at the L7 level. Lines at axon terminations indicate excitatory connections and circles indicate inhibitory connections. gr, gracile fasciculus; IMM, intermedio-medial nucleus; IO, inferior olive; LC, locus coeruleus; LSp, lateral spinal nucleus; PaR, pararubral nucleus; R, red nucleus; 7N, seventh nerve nucleus.

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