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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Michael Fritz
  • Anna M. Klawonn
  • Anna Nilsson
  • Anand Kumar Singh
  • Joanna Zajdel
  • Daniel Björk Wilhelms
  • Michael Lazarus
  • Andreas Löfberg
  • Maarit Jaarola
  • Unn Örtegren Kugelberg
  • Timothy R. Billiar
  • David J. Hackam
  • Chhinder P. Sodhi
  • Matthew D. Breyer
  • Markus Schwaninger
  • Günther Schütz
  • Jan Rodriguez Parkitna
  • Clifford B. Saper
  • Anders Blomqvist
  • David Engblom
Organisations
External organisations
  • Linköping University
  • University of Tsukuba
  • University of Pittsburgh Medical Center
  • Johns Hopkins University
  • Lilly Research Laboratories
  • University of Lübeck
  • German Cancer Research Centre
  • Polish Academy of Sciences
  • Harvard University
  • Beth Israel Deaconess Medical Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
Original languageEnglish
Pages (from-to)695-705
JournalJournal of Clinical Investigation
Volume126
Issue number2
Publication statusPublished - 2015 Dec 21
Publication categoryResearch
Peer-reviewedYes