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Locus coeruleus

Locus coeruleus

The locus coeruleus (caeruleal nucleus) regulates attention and is an important mediator of stress reactions.
It is activated by orexin and sends the noradrenaline it produces to a number of brain regions that are involved in stress systems. The locus coeruleus produces 95% of the noradrenaline in the brain and is therefore a key control element of the sympathetic nervous system.
In addition, the locus coeruleus controls the interactions between the serotonergic and noradrenergic systems.
Chronic activation of the locus coeruleus appears to reduce the stress response. Chemical deactivation of the locus coeruleus temporarily reduces the response of the HPA axis, but the response still returns after prolonged stress.

1. Behaviors regulated by locus coeruleus

The locus coeruleus is involved in the control of various behaviors:1

  • Attention
    • sustained attention
    • Attention control
    • (Mental) orientation in the sense of directed attention
  • Arousal
  • Stress reaction2
  • Memory
  • Regulation of the sleep stages
  • emotional mood
  • Sexual behavior
  • motor functions
    • in the striatum3

2. Activation, efferents, afferents of the locus coeruleus

The locus coeruleus is part of the formatio reticularis, is stimulated by orexin and produces noradrenaline.

Afferences (incoming signals) from:

  • MPFC
    • Constant stimulating input according to the activity level
  • Nucleus paragigantocellularis
    • Integrates autonomous stimuli and environmental stimuli
  • Nucleus prepositus perihypoglossalis
    • Controls horizontal and vertical eye movements, eye tracking movements and gaze fixation
  • Lateral hypothalamus
    • Produces orexin

Efferents (outgoing signals):
At least 6 different LC neuron groups send noradrenaline to different brain regions via at least 6 different pathways4

  1. Olfactory bulb
  2. Frontal cortex
  3. visual cortex
  4. Thalamus and midbrain
  5. Cerebellum
  6. Spinal cord

Efferences are also used:

  • Amygdala
  • Hippocampus
  • Brain stem
  • Motor cortex4
  • Hypothalamus
    • Paraventricular nucleus
  • Tectum (dorsal mesencephalon)
  • Thalamus
  • Ventral tegmentum
  • Neocortex
  • Inferior olive4
  • Striatum4
  • Caudate putamen4

It is unclear whether the LC cell groups are controlled jointly or individually by the incoming afferents, whether they control their outgoing efferents in a uniform or differentiated manner, whether different LC cell groups have different tasks and whether temporal differences in the firing signal differentiated meanings. There is increasing evidence that the LC does not act as a uniform structure and that the different C neuron groups have differentiated tasks.

3. Co-transmitters and co-peptides of the locus coeruleus

Co-transmitters in locus coeruleus cells include noradrenaline:4

  • Dopamine
  • Galanin
  • Neuropeptide Y
  • BDNF
  • Cocaine and amphetamine regulated transcript (CART)

4. Involvement of the locus coeruleus in diseases

The locus coeruleus is involved in various disorders, such as

  • ADHD4
  • Parkinson’s disease4
  • Down syndrome1
  • Alzheimer’s disease4
  • PTSD4
  • Anxiety disorders4
    • LC - Overactivity
  • Depression4
  • Drug effects and addiction1
  • Epilepsy4
  • Cognitive dysfunction4

5. Miscellaneous

Chronic activation of the locus coeruleus appears to reduce the stress response.5

Chemical deactivation of the locus coeruleus acutely and briefly reduced the response of the HPA axis. However, after 4 weeks of chronic stress, the HPA axis response was fully restored despite deactivated locus coeruleus .6 This indicates that the locus coeruleus appears to primarily mediate acute stress responses.

Sleep deprivation can lead to the death of locus coeruleus neurons.7

LC neurons are functionally active from birth and change postnatally. Noradrenaline is required for the development and survival of dopaminergic cells in the midbrain. Early loss of neurons in the locus coeruleus is a hallmark of Parkinson’s and other neurodegenerative diseases. Noradrenaline afferents via BDNF appear to provide trophic support for vulnerable midbrain dopamine neurons. The locus coeruleus of newborn and young organisms is rich in BDNF, which is essential for the neuronal survival of midbrain dopamine neurons8

Newborns appear to exhibit increased sensitivity of the LC to somatosensory stimuli, which diversifies later in development, resulting in a reduced response to innocuous stimuli and a more sensitive response to noxious stimuli.9 The enhanced neonatal LC response may underlie some unique features of infant learning, such as attachment10
A high level of maternal care influences the density of various receptors in the locus coeruleus in the direction of increased stress resistance:11

  • Benzodiazepine receptor (also in amygdala)
  • α2-adrenoreceptor
  • CRH receptor.

  1. Pschyrembel: Locus caeruleus

  2. Benarroch EE (2018): Locus coeruleus. Cell Tissue Res. 2018 Jul;373(1):221-232. doi: 10.1007/s00441-017-2649-1. PMID: 28687925. REVIEW

  3. Zerbi V, Floriou-Servou A, Markicevic M, Vermeiren Y, Sturman O, Privitera M, von Ziegler L, Ferrari KD, Weber B, De Deyn PP, Wenderoth N, Bohacek J (2019): Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation. Neuron. 2019 Aug 21;103(4):702-718.e5. doi: 10.1016/j.neuron.2019.05.034. PMID: 31227310.

  4. Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S, Aston-Jones G, Harley CW, Manahan-Vaughan D, Weinshenker D, Valentino R, Berridge C, Chandler DJ, Waterhouse B, Sara SJ (2020): Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci. 2020 Nov;21(11):644-659. doi: 10.1038/s41583-020-0360-9. PMID: 32943779; PMCID: PMC8991985. REVIEW

  5. Velley, Cardo, Kempf, Mormede, Nassif-Caudarella, Velly (1991): Facilitation of learning consecutive to electrical stimulation of the locus coeruleus: cognitive alteration or stress-reduction?. Prog Brain Res. 1991;88:555-569. doi:10.1016/s0079-6123(08)63834-0

  6. Ziegler DR, Cass WA, Herman JP (1999): Excitatory influence of the locus coeruleus in hypothalamic-pituitary-adrenocortical axis responses to stress. J Neuroendocrinol. 1999;11(5):361-369. doi:10.1046/j.1365-2826.1999.00337.x

  7. Zamore Z, Veasey SC (2022): Neural consequences of chronic sleep disruption. Trends Neurosci. 2022 Sep;45(9):678-691. doi: 10.1016/j.tins.2022.05.007. PMID: 35691776; PMCID: PMC9388586.

  8. Hassani OK, Rymar VV, Nguyen KQ, Huo L, Cloutier JF, Miller FD, Sadikot AF (2020): The noradrenergic system is necessary for survival of vulnerable midbrain dopaminergic neurons: implications for development and Parkinson’s disease. Neurobiol Aging. 2020 Jan;85:22-37. doi: 10.1016/j.neurobiolaging.2019.09.014. PMID: 31734438.

  9. Nakamura S, Kimura F, Sakaguchi T (1987): Postnatal development of electrical activity in the locus ceruleus. J Neurophysiol. 1987 Sep;58(3):510-24. doi: 10.1152/jn.1987.58.3.510. PMID: 3655880.

  10. Debiec J, Sullivan RM (2017): The neurobiology of safety and threat learning in infancy. Neurobiol Learn Mem. 2017 Sep;143:49-58. doi: 10.1016/j.nlm.2016.10.015. PMID: 27826033; PMCID: PMC5418109.

  11. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ (1998): Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5335-40. doi: 10.1073/pnas.95.9.5335. PMID: 9560276; PMCID: PMC20261.

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