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

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 infl...

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Published in:	The Journal of clinical investigation Vol. 126; no. 2; pp. 695 - 705
Main Authors:	Fritz, Michael, Klawonn, Anna M., Nilsson, Anna, Singh, Anand Kumar, Zajdel, Joanna, Björk Wilhelms, Daniel, Lazarus, Michael, Löfberg, Andreas, Jaarola, Maarit, Örtegren Kugelberg, Unn, Billiar, Timothy R., Hackam, David J., Sodhi, Chhinder P., Breyer, Matthew D., Jakobsson, Johan, Schwaninger, Markus, Schütz, Günther, Rodriguez Parkitna, Jan, Saper, Clifford B., Blomqvist, Anders, Engblom, David
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01.02.2016
Subjects:	Animals Basic Medicine Biomedical research Brain - metabolism Brain - pathology Brain Diseases - genetics Brain Diseases - metabolism Brain Diseases - pathology Brain research Cell Line Councils Cyclooxygenase 1 - genetics Cyclooxygenase 1 - metabolism Dinoprostone - genetics Dinoprostone - metabolism Dopaminergic mechanisms Dopaminergic Neurons - metabolism Dopaminergic Neurons - pathology Endothelium Endothelium, Vascular - metabolism Endothelium, Vascular - pathology Experiments Health aspects Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Medical and Health Sciences Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Knockout Neural transmission Neurosciences Neurovetenskaper Physiological aspects Properties Prostaglandins Receptors, Dopamine D1 - genetics Receptors, Dopamine D1 - metabolism Rodents Social research Synaptic Transmission
ISSN:	0021-9738, 1558-8238, 1558-8238
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Summary:	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.
Bibliography:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Authorship note: M. Fritz and A.M. Klawonn contributed equally to this work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI83844