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Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Fritz, Michael ; Klawonn, Anna M.; Nilsson, Anna; Singh, Anand Kumar; Zajdel, Joanna; Björk Wilhelms, Daniel; Lazarus, Michael; Löfberg, Andreas; Jaarola, Maarit and Örtegren Kugelberg, Unn, et al. (2015) In Journal of Clinical Investigation 126(2). p.695-705
Abstract
Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral... (More)
Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation. (Less)
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published
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Journal of Clinical Investigation
volume
126
issue
2
pages
695 - 705
publisher
The Journal of Clinical Investigation
external identifiers
  • scopus:84956891725
ISSN
0021-9738
DOI
10.1172/JCI83844
language
English
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yes
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be312a2d-3392-4a27-8858-f939193bcdf4
date added to LUP
2016-11-18 11:18:12
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2017-09-10 05:11:52
@article{be312a2d-3392-4a27-8858-f939193bcdf4,
  abstract     = {Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.},
  author       = {Fritz, Michael  and Klawonn, Anna M. and Nilsson, Anna and Singh, Anand Kumar and Zajdel, Joanna and Björk Wilhelms, Daniel and Lazarus, Michael and Löfberg, Andreas and Jaarola, Maarit and Örtegren Kugelberg, Unn and Billiar, Timothy R. and Hackam, David J.  and Sodhi, Chhinder P. and Breyer, Matthew D.  and Jakobsson, Johan and Schwaninger, Markus and Schütz, Günther  and Rodriguez Parkitna, Jan and Saper, Clifford B.  and Blomqvist, Anders and Engblom, David},
  issn         = {0021-9738},
  language     = {eng},
  month        = {12},
  number       = {2},
  pages        = {695--705},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice},
  url          = {http://dx.doi.org/10.1172/JCI83844},
  volume       = {126},
  year         = {2015},
}