Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
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, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom
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, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom
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Research Article Neuroscience

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.

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, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom

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Figure 2

Inflammatory aversion is driven by MyD88-dependent signaling in the brain endothelium.

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Inflammatory aversion is driven by MyD88-dependent signaling in the brai...
(A) Recombination specific to CD31-positive brain endothelial cells visualized using a reporter line. (B and C) Mice lacking MyD88 in brain endothelial cells (Myd88ΔbEnd) do not demonstrate place aversion in response to LPS (n = 6, WT; 7, Myd88ΔbEnd) (B) or IL-1β (n = 6, WT; 8, Myd88ΔbEnd) (C) injections i.p. (D) In contrast, mice lacking MyD88 in myeloid cells display an aversive response to LPS. (E–G) Mice given an IL-1R antagonist i.p. (n = 6, WT; 6, IL-1R antagonist; E), mice lacking caspase-1 (n = 6, WT; 6, Casp1 KO; F), and mice lacking IL-1Rs (Il1r KO; n = 13, WT; 14, Il1r KO; G), develop normal avoidance of the chamber paired with LPS injections, as do mice lacking the TNFα receptors 1 and 2 (n = 7; G). In contrast, mice lacking both TNFα receptor 1 and the IL-1R display a blunted aversive response (n = 8; G). (H) Mice with deletion of TLR4 selectively in the brain endothelium (Tlr4ΔbEnd) do not demonstrate place aversion in response to LPS i.p. (n = 5, WT; 5, Tlr4ΔbEnd). Scale bar: 100 μm. *P < 0.05, **P < 0.01, Student’s t test (B–F and H) or 1-way ANOVA followed by Dunnett’s post hoc test (G).