Locus coeruleus

The locus coeruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the central nervous system. The LC-NE system has a major role in arousal, attention and stress responses. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis and control of local blood flow. The LC is severely affected in neurodegenerative disorders including Parkinson disease (PD). Involvement of the noradrenergic neurons of the LC precedes that of dopaminergic neurons of the substantia nigra pars compacta and has been increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly impaired attention. Abnormal noradrenergic signaling may also potentially contribute to motor manifestations of the disease.This makes the LC-NE system a major contributor to the pathobiology and potential target for therapy of PD.

[1]  D. Surmeier,et al.  Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase , 2014, Nature Neuroscience.

[2]  Roger A. Barker,et al.  Targeting impulsivity in Parkinson’s disease using atomoxetine , 2014, Brain : a journal of neurology.

[3]  W. Poewe,et al.  The Movement Disorder Society Evidence‐Based Medicine Review Update: Treatments for the non‐motor symptoms of Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[4]  D. McCormick,et al.  Neurotransmitter actions in the thalamus and cerebral cortex. , 1992, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[5]  Suneil K. Kalia,et al.  The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease , 2015, The European journal of neuroscience.

[6]  Xin Wang,et al.  Optogenetic Stimulation of Locus Ceruleus Neurons Augments Inhibitory Transmission to Parasympathetic Cardiac Vagal Neurons via Activation of Brainstem α1 and β1 Receptors , 2014, The Journal of Neuroscience.

[7]  C. Brayne,et al.  Depression in the elderly: pathological study of raphe and locus ceruleus , 2005, Neuropathology and applied neurobiology.

[8]  Luca Mainardi,et al.  Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease , 2016, Front. Aging Neurosci..

[9]  T. Robbins,et al.  Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson's disease. , 1993, Brain : a journal of neurology.

[10]  Antoine Adamantidis,et al.  Sleep Homeostasis Modulates Hypocretin-Mediated Sleep-to-Wake Transitions , 2009, The Journal of Neuroscience.

[11]  Ee Peng Lim,et al.  Locus coeruleus stimulation and noradrenergic modulation of hippocampo-prefrontal cortex long-term potentiation. , 2010, The international journal of neuropsychopharmacology.

[12]  Daniel O'Connor,et al.  Laminar, tangential and regional organization of the noradrenergic innervation of monkey cortex: Dopamine-β-hydroxylase immunohistochemistry , 1982, Brain Research Bulletin.

[13]  Shosuke Ito,et al.  Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus , 2015, Journal of neurochemistry.

[14]  S. Kish,et al.  Thalamic noradrenaline in Parkinson's disease: Deficits suggest role in motor and non‐motor symptoms , 2012, Movement disorders : official journal of the Movement Disorder Society.

[15]  Wenjun Gao,et al.  Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex , 2016, Brain Research.

[16]  J. D. McGaugh,et al.  Memory modulation. , 2011, Behavioral neuroscience.

[17]  Abdelhamid Benazzouz,et al.  Noradrenaline and Parkinson's Disease , 2011, Front. Syst. Neurosci..

[18]  R. Dolan,et al.  Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Björklund,et al.  Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease , 2014, Experimental Neurology.

[20]  Qingshan Wang,et al.  A novel role of microglial NADPH oxidase in mediating extra‐synaptic function of norepinephrine in regulating brain immune homeostasis , 2015, Glia.

[21]  Dorothee P Auer,et al.  In Vivo Assessment of Brainstem Depigmentation in Parkinson Disease: Potential as a Severity Marker for Multicenter Studies. , 2017, Radiology.

[22]  Chris Zarow,et al.  Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. , 2003, Archives of neurology.

[23]  R. Takahashi,et al.  Immunohistochemical localization of apoptosome-related proteins in Lewy bodies in Parkinson׳s disease and dementia with Lewy bodies , 2014, Brain Research.

[24]  Peter A LeWitt,et al.  Norepinephrine: the next therapeutics frontier for Parkinson's disease , 2012, Translational Neurodegeneration.

[25]  K. Rommelfanger,et al.  Norepinephrine: The redheaded stepchild of Parkinson's disease. , 2007, Biochemical pharmacology.

[26]  J. Cohen,et al.  The role of locus coeruleus in the regulation of cognitive performance. , 1999, Science.

[27]  W. Hare,et al.  Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. , 2008, Investigative ophthalmology & visual science.

[28]  J. Aceves,et al.  Noradrenaline increases the firing rate of a subpopulation of rat subthalamic neurones through the activation of α1-adrenoceptors , 2003, Neuropharmacology.

[29]  Roger A. Barker,et al.  Improving Response Inhibition in Parkinson’s Disease with Atomoxetine , 2015, Biological Psychiatry.

[30]  K. Kendrick,et al.  Human amygdala reactivity is diminished by the β-noradrenergic antagonist propranolol , 2010, Psychological Medicine.

[31]  P. Crenna,et al.  Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease , 2011, BMC neurology.

[32]  David J. Brooks,et al.  Progression of monoaminergic dysfunction in Parkinson's disease: A longitudinal 18F-dopa PET study , 2011, NeuroImage.

[33]  M. Nedergaard,et al.  Distinct Functional States of Astrocytes During Sleep and Wakefulness: Is Norepinephrine the Master Regulator? , 2015, Current Sleep Medicine Reports.

[34]  P. Goldman-Rakic,et al.  Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey , 1984, Brain Research.

[35]  P. Sawchenko,et al.  Noradrenergic Innervation of the Dorsal Medial Prefrontal Cortex Modulates Hypothalamo-Pituitary-Adrenal Responses to Acute Emotional Stress , 2008, The Journal of Neuroscience.

[36]  Jisook Moon,et al.  Alpha-synuclein interferes with cAMP/PKA-dependent upregulation of dopamine β-hydroxylase and is associated with abnormal adaptive responses to immobilization stress , 2014, Experimental Neurology.

[37]  H. Braak,et al.  Lewy pathology and neurodegeneration in premotor Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[38]  S. Foote,et al.  Distribution of dopamine β‐hydroxylase‐like immunoreactive fibers within the shell subregion of the nucleus accumbens , 1997, Synapse.

[39]  Y. Agid,et al.  Idazoxan, an alpha‐2 antagonist, and L‐DOPA‐induced dyskinesias in patients with Parkinson's disease , 2001, Movement disorders : official journal of the Movement Disorder Society.

[40]  Tadeusz Sarna,et al.  Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease , 2017, Progress in Neurobiology.

[41]  D. Qiu,et al.  Effects of norepinephrine on spontaneous firing activity of cerebellar Purkinje cells in vivo in mice , 2016, Neuroscience Letters.

[42]  W. Drinkenburg,et al.  Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model , 2014, Behavioural Brain Research.

[43]  A. Russo-Neustadt,et al.  Norepinephrine and nitric oxide promote cell survival signaling in hippocampal neurons. , 2010, European journal of pharmacology.

[44]  R. Wise,et al.  Dopamine Uptake through the Norepinephrine Transporter in Brain Regions with Low Levels of the Dopamine Transporter: Evidence from Knock-Out Mouse Lines , 2002, The Journal of Neuroscience.

[45]  Y. Smith,et al.  Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys , 2017, Neurobiology of Disease.

[46]  David P. Friedman,et al.  Norepinephrinergic afferents and cytology of the macaque monkey midline, mediodorsal, and intralaminar thalamic nuclei , 2008, Brain Structure and Function.

[47]  K. Ressler,et al.  Role of Norepinephrine in the Pathophysiology of Neuropsychiatric Disorders , 2001, CNS Spectrums.

[48]  Megan M. Risi,et al.  Frontal and posterior subtypes of neuropsychological deficit in Parkinson's disease. , 2013, Behavioral neuroscience.

[49]  K. Fuxe,et al.  Localization of monoamines in the lower brain stem , 1964, Experientia.

[50]  E. Bézard,et al.  Effect of the α2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey , 1999, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[51]  Eduardo E. Benarroch,et al.  The locus ceruleus norepinephrine system , 2009, Neurology.

[52]  J. Kulisevsky,et al.  Effect of the additional noradrenergic neurodegeneration to 6-OHDA-lesioned rats in levodopa-induced dyskinesias and in cognitive disturbances , 2009, Journal of Neural Transmission.

[53]  C. Marín,et al.  Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats , 2008, Journal of Neural Transmission.

[54]  D. Surmeier,et al.  A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[55]  Angela J. Yu,et al.  Phasic norepinephrine: A neural interrupt signal for unexpected events , 2006, Network.

[56]  T. McHugh,et al.  Noradrenergic modulation of evoked dopamine release and pH shift in the mouse dorsal hippocampus and ventral striatum , 2017, Brain Research.

[57]  E. Lindberg,et al.  Differential degeneration of the locus coeruleus in dementia subtypes. , 2011, Clinical neuropathology.

[58]  S. Kalinin,et al.  Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta , 2007, Journal of neurochemistry.

[59]  Denise Manahan-Vaughan,et al.  β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory , 2016, Cerebral cortex.

[60]  M. Palkovits,et al.  Peptidergic innervation of the locus coeruleus cells in the human brain , 1990, Brain Research.

[61]  M. Atzori,et al.  Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation? , 2016, Front. Synaptic Neurosci..

[62]  G. Chrousos Stress and disorders of the stress system , 2009, Nature Reviews Endocrinology.

[63]  A. Benazzouz,et al.  Activation of subthalamic alpha 2 noradrenergic receptors induces motor deficits as a consequence of neuronal burst firing , 2012, Neurobiology of Disease.

[64]  G. Miller,et al.  Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice , 2007, Proceedings of the National Academy of Sciences.

[65]  B. Waterhouse,et al.  Reciprocal connections between subdivisions of the dorsal raphe and the nuclear core of the locus coeruleus in the rat , 2004, Brain Research.

[66]  O. Lindvall,et al.  The organization of the ascending catecholamine neuron systems in the rat brain as revealed by the glyoxylic acid fluorescence method. , 1974, Acta physiologica Scandinavica. Supplementum.

[67]  Yasuo Terayama,et al.  Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. , 2014, Parkinsonism & related disorders.

[68]  S. Sara,et al.  Network reset: a simplified overarching theory of locus coeruleus noradrenaline function , 2005, Trends in Neurosciences.

[69]  D. Lindenbach,et al.  Effects of noradrenergic denervation by anti-DBH-saporin on behavioral responsivity to l-DOPA in the hemi-parkinsonian rat , 2014, Behavioural Brain Research.

[70]  Marie Vidailhet,et al.  The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. , 2016, Brain : a journal of neurology.

[71]  V. Chan‐Palay,et al.  Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression , 1989, The Journal of comparative neurology.

[72]  C. Berridge,et al.  The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes , 2003, Brain Research Reviews.

[73]  J. Morrison,et al.  Noradrenergic innervation of the hypothalamus of rhesus monkeys: Distribution of dopamine‐β‐hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus , 1993, The Journal of comparative neurology.

[74]  Habib Benali,et al.  The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease , 2013, Brain : a journal of neurology.

[75]  Georg Auburger,et al.  The Brainstem Pathologies of Parkinson's Disease and Dementia with Lewy Bodies , 2015, Brain pathology.

[76]  E. Peskind,et al.  Preservation of Noradrenergic Neurons in the Locus Ceruleus that Coexpress Galanin mRNA in Alzheimer's Disease , 1999, Journal of neurochemistry.

[77]  Yasuo Terayama,et al.  Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging , 2013, Neuroscience Letters.

[78]  P. Luppi,et al.  New aspects in the pathophysiology of rapid eye movement sleep behavior disorder: the potential role of glutamate, gamma-aminobutyric acid, and glycine. , 2013, Sleep medicine.

[79]  B. Berger,et al.  Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine‐beta‐hydroxylase , 1989, The Journal of comparative neurology.

[80]  Wade K. Smith,et al.  Disease‐specific patterns of locus coeruleus cell loss , 1992, Annals of neurology.

[81]  D. Bennett,et al.  Brainstem aminergic nuclei and late-life depressive symptoms. , 2013, JAMA psychiatry.

[82]  Qunyuan Xu,et al.  Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial function in mouse models of Parkinson׳s disease , 2015, Brain Research.

[83]  W. Oertel,et al.  A concerted action of L- and T-type Ca2+ channels regulates locus coeruleus pacemaking , 2015, Molecular and Cellular Neuroscience.

[84]  A. Lees,et al.  Cognitive deficits in the early stages of Parkinson's disease. , 1983, Brain : a journal of neurology.

[85]  P. Bonaventure,et al.  OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2‐INDUCED PANIC‐ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES , 2015, Depression and anxiety.

[86]  Y. Miyashita,et al.  Medial prefrontal activity during shifting under novel situations , 2010, Neuroscience Letters.

[87]  T. Horvath,et al.  Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque , 2007, Neurobiology of Aging.

[88]  G. Leichnetz Afferent and efferent connections of the dorsolateral precentral gyrus (area 4, hand/arm region) in the macaque monkey, with comparisons to area 8 , 1986, The Journal of comparative neurology.

[89]  T. Joh,et al.  Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease , 1990, Annals of neurology.

[90]  G. Paxinos,et al.  The substantia nigra and ventral tegmental dopaminergic neurons from development to degeneration , 2016, Journal of Chemical Neuroanatomy.

[91]  Wade G. Regehr,et al.  Noradrenergic Control of Associative Synaptic Plasticity by Selective Modulation of Instructive Signals , 2009, Neuron.

[92]  J. Morrison,et al.  Noradrenergic innervation of monkey prefrontal cortex: A dopamine‐β‐hydroxylase immunohistochemical study , 1989, The Journal of comparative neurology.

[93]  H. Eichenbaum,et al.  Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting , 2008, Neuroscience.

[94]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[95]  F. Colpaert,et al.  Effects of (+/-)-idazoxan alone and in combination with L-DOPA methyl ester in MPTP-induced hemiparkinsonian monkeys. , 2003, Receptors & channels.

[96]  H. Groenewegen,et al.  The Proteome of the Locus Ceruleus in Parkinson's Disease: Relevance to Pathogenesis , 2012, Brain pathology.

[97]  S. Lewis,et al.  Pathology of behavior in PD : What is known and what is not ? , 2022 .

[98]  A. C. Roberts,et al.  Impaired extra-dimensional shift performance in medicated and unmedicated Parkinson's disease: Evidence for a specific attentional dysfunction , 1989, Neuropsychologia.

[99]  U. Ungerstedt,et al.  Noradrenaline Nerve Terminals in Human Cerebral Cortices: First Histochemical Evidence , 1972, Science.

[100]  Hye-Sun Kim,et al.  Norepinephrine provides short-term neuroprotection against Aβ1–42 by reducing oxidative stress independent of Nrf2 activation , 2014, Neurobiology of Aging.

[101]  B D Waterhouse,et al.  New perspectives on the functional organization and postsynaptic influences of the locus ceruleus efferent projection system. , 1998, Advances in pharmacology.

[102]  E. Bézard,et al.  Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats , 2007, The Journal of Neuroscience.

[103]  Udo Rüb,et al.  Where Does Parkinson Disease Pathology Begin in the Brain? , 2002, Journal of neuropathology and experimental neurology.

[104]  A. Arnsten,et al.  Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses , 2012, Neuron.

[105]  A. Erisir,et al.  Monosynaptic Glutamatergic Activation of Locus Coeruleus and Other Lower Brainstem Noradrenergic Neurons by the C1 Cells in Mice , 2013, The Journal of Neuroscience.

[106]  Xiaoping Hu,et al.  Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. , 2014, Magnetic resonance imaging.

[107]  Jian Liu,et al.  Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism , 2009, Neuroscience bulletin.

[108]  K. Ye,et al.  Norepinephrine Protects against Amyloid-beta Toxicity via TrkB , 2022 .

[109]  M. Raskind,et al.  Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson's disease and Alzheimer's disease , 2011, Brain Research.

[110]  M. Husain,et al.  Noradrenergic modulation of space exploration in visual neglect , 2006, Annals of neurology.

[111]  M. Corbetta,et al.  The Reorienting System of the Human Brain: From Environment to Theory of Mind , 2008, Neuron.

[112]  S. Foote,et al.  Noradrenergic and serotoninergic innervation of cortical, thalamic, and tectal visual structures in old and new world monkeys , 1986, The Journal of comparative neurology.

[113]  S Patt,et al.  A Golgi study of human locus coeruleus in normal brains and in Parkinson's disease , 1993, Neuropathology and applied neurobiology.

[114]  Nora Turjanski,et al.  Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. , 2005, Brain : a journal of neurology.

[115]  S. Foote,et al.  Extrathalamic modulation of cortical function. , 1987, Annual review of neuroscience.

[116]  C. Tai,et al.  Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control. , 2016, The Journal of clinical investigation.

[117]  W. Schmidt,et al.  Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6‐hydroxydopamine‐induced partial degeneration of substantia nigra in rats , 2003, The European journal of neuroscience.

[118]  U. Schambra,et al.  Neuron specific α-adrenergic receptor expression in human cerebellum: Implications for emerging cerebellar roles in neurologic disease , 2005, Neuroscience.

[119]  T. Robbins,et al.  Functions of frontostriatal systems in cognition: Comparative neuropsychopharmacological studies in rats, monkeys and humans , 2006, Biological Psychology.

[120]  F. Tempia,et al.  Noradrenergic modulation of the parallel fiber-Purkinje cell synapse in mouse cerebellum , 2015, Neuropharmacology.

[121]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[122]  Mark A. Eckert,et al.  Histologic validation of locus coeruleus MRI contrast in post-mortem tissue , 2015, NeuroImage.

[123]  A. Parent,et al.  The monoaminergic innervation of the amygdala in the squirrel monkey: An immunohistochemical study , 1990, Neuroscience.

[124]  G. Miller,et al.  Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus , 2014, Neuropharmacology.

[125]  Gary Aston-Jones,et al.  The emerging role of norepinephrine in cognitive dysfunctions of Parkinson's disease , 2012, Front. Behav. Neurosci..

[126]  Hiroshi Fukuda,et al.  Attentional Set-Shifting Deficit in Parkinson’s Disease Is Associated with Prefrontal Dysfunction: An FDG-PET Study , 2012, PloS one.

[127]  J. D. Coulter,et al.  Descending projections of the locus coeruleus and subcoeruleus/medial parabrachial nuclei in monkey: Axonal transport studies and dopamine-β-hydroxylase immunocytochemistry , 1980, Brain Research Reviews.

[128]  Jun Lu,et al.  Locus Ceruleus and Anterior Cingulate Cortex Sustain Wakefulness in a Novel Environment , 2010, The Journal of Neuroscience.

[129]  J. Allman,et al.  Comparative anatomy of the locus coeruleus in humans and nonhuman primates , 2010, The Journal of comparative neurology.

[130]  V. Fung,et al.  Unilateral rest tremor in vascular parkinsonism associated with a contralateral lesion of the locus coeruleus , 2009, Movement disorders : official journal of the Movement Disorder Society.

[131]  A. Craig,et al.  Association of spinal lamina I projections with brainstem catecholamine neurons in the monkey , 1996, Experimental Brain Research.

[132]  M. Vila,et al.  Selective noradrenergic vulnerability in alpha-synuclein transgenic mice , 2010, Neurobiology of Aging.