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Brain: Locus coeruleus
Rhomboid fossa. (Locus coeruleus not labeled, but region is very near colliculus facialis, which is labeled at center left.)
Latin	locus caeruleus
Gray's	subject #187 778
NeuroNames	hier-578
NeuroLex ID	birnlex_905

The Locus coeruleus, also spelled locus caeruleus, is a nucleus in the brain stem involved with physiological responses to stress and panic. It was discovered in the 1700s by Félix Vicq-d'Azyr.

Its name is derived from the Latin words "caeruleus" and "locus" meaning, literally, "the blue spot" due to its somewhat azure appearance in unstained brain tissue. Caeruleus is the classical Latin spelling, but coeruleus, a more archaic form, is the more common spelling. The spelling ceruleus, formed by contraction of the digraph ae or oe into e, is an American English form.

Contents 1 Anatomy 2 Connections 3 Function 3.1 In stress 3.2 In opiate withdrawal 3.3 Rett syndrome 4 See also 5 References 6 External links

[edit] Anatomy

The locus coeruleus (or "LC") is located within the dorsal wall of the rostral pons in the lateral floor of the fourth ventricle. This nucleus is the principal site for synthesis of noradrenaline (norepinephrine) in the brain, and is composed of mostly medium-size neurons. Melanin granules inside the LC contribute to its blue color; it is thereby 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 neuron that range in size between 31,000 to 60, 000 μm³.^[1]

[edit] Connections

The projections of this nucleus reach far and wide, innervating the spinal cord, the brain stem, cerebellum, hypothalamus, the 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. It has been said that a single noradrenergic neuron can innervate the entire cerebral cortex via its branches.

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, particularly the raphe pontis and raphe 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 prepositus hypoglossi, which is involved in gaze
• Lateral hypothalamus, which releases orexin, which, as well as its other functions, is excitatory in the locus coeruleus.

[edit] Function

The locus coeruleus is studied in relation to clinical depression, panic disorder, and anxiety. Some antidepressant medications including reboxetine, venlafaxine, and bupropion, as well as ADHD medication atomoxetine, are believed to act on neurons in this area. This area of the brain is also intimately involved in REM sleep.

Psychiatric research has documented that enhanced noradrenergic postsynaptic responsiveness in the neuronal pathway (brain circuit) that originates in the locus coeruleus and end 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). The LC neurons are probably the origin of the first or second “leg” of what has been recently termed the "PTSD candidate circuit." Combat-related PTSD (in a 2005 study of deceased American army veterans from World War II) was shown to be associated with a postmortem diminished number of neurons in the locus coeruleus (LC) on the right side of the brain.^[2] The role of the LC in PTSD may explain the dramatic effectiveness of two generic medications, propranolol and prazosin for the secondary prevention and treatment of PTSD, respectively.^{[citation needed]}

[edit] 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 increase 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.^{[citation needed]}

[edit] 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.^{[citation needed]}

[edit] Rett syndrome

The genetic defect of the transcriptional regulator MECP2 is responsible for Rett syndrome^[3]. A MeCP2 deficiency has been associated to catecholaminergic dysfunctions related to autonomic and sympathoadrenergic system in mouse models of RTT. The Locus Coeruleus is the major source of noradrenergic innervation in the brain and send widespread connections to rostral (cerebral cortex, hippocampus, hypothalamus) and caudal (cerebellum, brainstem nuclei) brain areas^[4] and ^[5]. 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.^[6]. Interestingly, 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 surounding the structure was shown in symptomatic Mecp2-deficient mice^[7]. However, locus coeruleus cells are not dying but are more likely loosing their fully mature phenotype since no apoptotic neurons in the pons were detected^[7]. 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^[6]. This could explain why a norepinephrine reuptake inhibitor (desipramine, DMI) which enhance the extracellular NE levels at all noradrenergic synapses could ameliorates some symptoms in a mouse model of Rett Syndrome^[7].

[edit] See also

• Raphe nucleus
• Substantia nigra
• Reticular formation

[edit] References

1. ^ Mouton PR, Pakkenberg B, Gundersen HJ, Price DL. (1994). Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals. J Chem Neuroanat. 7(3):185-90. PMID 7848573
2. ^ Bracha HS, Garcia-Rill E, Mrak RE, Skinner R (2005). "Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD". The Journal of neuropsychiatry and clinical neurosciences 17 (4): 503–9. doi:10.1176/appi.neuropsych.17.4.503. PMID 16387990. 
3. ^ 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
4. ^ 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.
5. ^ 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
6. ^ ^{a b} Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB. (2009). Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome. Journal of Neuroscience, 29(39):12187–12195. doi:10.1523/JNEUROSCI.3156-09.2009
7. ^ ^{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 http://www3.interscience.wiley.com/cgi-bin/fulltext/123208150/HTMLSTART

[edit] External links

• "A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness" at East Tennessee State University
• BrainMaps at UCDavis locus coeruleus

• Diagram at University of Texas at Austin
• Diagram at University of Virginia
• http://www2.umdnj.edu/~neuro/studyaid/Practical2000/Q45.htm

v • d • e Human brain, rhombencephalon, metencephalon: pons (TA A14.1.05.101-604, GA 9.785) Dorsal/ (tegmentum) Surface Cerebellopontine angle · Superior medullary velum · Sulcus limitans · Medial eminence · Facial colliculus White: Sensory/ascending Trapezoid body/VIII · Trigeminal lemniscus (Dorsal trigeminal tract, Ventral trigeminal tract) · Medial lemniscus · Lateral lemniscus MLF, III, IV and VI: Vestibulo-oculomotor fibers Anterior trigeminothalamic tract · Central tegmental tract White: Motor/descending ICP (Vestibulocerebellar tract) MLF, III, IV and VI: Vestibulospinal tract (Medial vestibulospinal tract, Lateral vestibulospinal tract) Grey: Cranial nuclei afferent: GSA: Principal V/Spinal V · VIII-c (Dorsal, Anterior)/VIII-v (Superior) efferent: SVE: Motor V  · VII · GSE: VI · GVE: VII: Superior salivary nucleus Other grey Apneustic center · Pneumotaxic center (Medial parabrachial nucleus) · Lateral parabrachial nucleus · Superior olivary nucleus · Caerulean nucleus Ventral/ (base) Grey Pontine nuclei White: Motor/descending Corticospinal tract · Corticobulbar tract · Corticopontine fibers MCP (Pontocerebellar fibers) Surface Basilar sulcus Other grey: Raphe/ reticular Reticular formation (Caudal, Oral, Tegmental, Paramedian) · Raphe nuclei (Median)

v • d • e Ventricular system, rhombencephalon, met- and myel-: fourth ventricle (TA A14.1.05.701-726, GA 9.797) Roof (dorsal) rostral: Superior medullary velum (Frenulum) caudal: Inferior medullary velum · Taenia of fourth ventricle Floor/rhomboid fossa (ventral) rostral (pons): Facial colliculus · Locus coeruleus caudal (medulla}: Vagal trigone · Hypoglossal trigone · Area postrema · Obex Medial eminence · Sulcus limitans Apertures Median/Magendie · Lateral recess to Lateral/Luschka Other Tela chorioidea of fourth ventricle · Fastigium

v • d • e Neurotransmitter systems Acetylcholine Basal optic nucleus of Meynert → Neocortex Septal nuclei (Medial septal nucleus) → Fornix → Hippocampus Striatum BA/M Dopaminergic pathways Mesocortical pathway: Ventral tegmental area → Frontal cortex Mesolimbic pathway: Ventral tegmental area → Nucleus accumbens Nigrostriatal pathway: Pars compacta → Striatum Tuberoinfundibular pathway: Hypothalamus → Pituitary gland Norepinephrine Locus coeruleus Serotonin pathways Raphe nuclei · Anterior raphespinal tract · Lateral raphespinal tract AA Aspartate Climbing fibers GABA Globus pallidus Glycine Renshaw cells Glutamate Thalamus · Subthalamic nucleus · Globus pallidus