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The Journal of Clinical Investigation
Article . 2015 . Peer-reviewed
Data sources: Crossref
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Europe PubMed Central
Other literature type . 2015
Data sources: PubMed Central
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Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Authors: Michael, Fritz; Anna M, Klawonn; Anna, Nilsson; Anand Kumar, Singh; Joanna, Zajdel; Daniel Björk, Wilhelms; Michael, Lazarus; +14 Authors

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

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.

Subjects by Vocabulary

Microsoft Academic Graph classification: Prostaglandin Inflammation Anorexia Systemic inflammation Malaise chemistry.chemical_compound Dopaminergic Cell medicine Prostaglandin E2 business.industry Dopaminergic chemistry Anesthesia Immunology medicine.symptom business medicine.drug

Keywords

Synaptic Transmission, Dinoprostone, Cell Line, Mice, Animals, Inflammation, Mice, Knockout, Brain Diseases, Dopaminergic Neurons, Receptors, Dopamine D1, Brain, Membrane Proteins, General Medicine, Cyclooxygenase 1, Endothelium, Vascular, Research Article

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    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
  • citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    58
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
58
Top 10%
Top 10%
Top 10%
Green
gold
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WT
Project
  • Funder: Wellcome Trust (WT)
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Neuroinformatics
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