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

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Standard

Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. / Fritz, Michael; Klawonn, Anna M; Nilsson, Anna; Singh, Anand Kumar; Zajdel, Joanna; Wilhelms, Daniel Björk; Lazarus, Michael; Löfberg, Andreas; Jaarola, Maarit; Kugelberg, Unn Örtegren; Billiar, Timothy R; Hackam, David J; Sodhi, Chhinder P; Breyer, Matthew D; Jakobsson, Johan; Schwaninger, Markus; Schütz, Günther; Parkitna, Jan Rodriguez; Saper, Clifford B; Blomqvist, Anders; Engblom, David.

I: The Journal of Clinical Investigation, Bind 126, Nr. 2, 02.2016, s. 695-705.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Fritz, M, Klawonn, AM, Nilsson, A, Singh, AK, Zajdel, J, Wilhelms, DB, Lazarus, M, Löfberg, A, Jaarola, M, Kugelberg, UÖ, Billiar, TR, Hackam, DJ, Sodhi, CP, Breyer, MD, Jakobsson, J, Schwaninger, M, Schütz, G, Parkitna, JR, Saper, CB, Blomqvist, A & Engblom, D 2016, 'Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice', The Journal of Clinical Investigation, bind 126, nr. 2, s. 695-705. https://doi.org/10.1172/JCI83844

APA

Fritz, M., Klawonn, A. M., Nilsson, A., Singh, A. K., Zajdel, J., Wilhelms, D. B., Lazarus, M., Löfberg, A., Jaarola, M., Kugelberg, U. Ö., Billiar, T. R., Hackam, D. J., Sodhi, C. P., Breyer, M. D., Jakobsson, J., Schwaninger, M., Schütz, G., Parkitna, J. R., Saper, C. B., ... Engblom, D. (2016). Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. The Journal of Clinical Investigation, 126(2), 695-705. https://doi.org/10.1172/JCI83844

Vancouver

Fritz M, Klawonn AM, Nilsson A, Singh AK, Zajdel J, Wilhelms DB o.a. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. The Journal of Clinical Investigation. 2016 feb.;126(2):695-705. https://doi.org/10.1172/JCI83844

Author

Fritz, Michael ; Klawonn, Anna M ; Nilsson, Anna ; Singh, Anand Kumar ; Zajdel, Joanna ; Wilhelms, Daniel Björk ; Lazarus, Michael ; Löfberg, Andreas ; Jaarola, Maarit ; Kugelberg, Unn Örtegren ; Billiar, Timothy R ; Hackam, David J ; Sodhi, Chhinder P ; Breyer, Matthew D ; Jakobsson, Johan ; Schwaninger, Markus ; Schütz, Günther ; Parkitna, Jan Rodriguez ; Saper, Clifford B ; Blomqvist, Anders ; Engblom, David. / Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. I: The Journal of Clinical Investigation. 2016 ; Bind 126, Nr. 2. s. 695-705.

Bibtex

@article{3566412575334c85aa50f9b060502627,
title = "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.",
keywords = "Animals, Brain/metabolism, Brain Diseases/genetics, Cell Line, Cyclooxygenase 1/genetics, Dinoprostone/genetics, Dopaminergic Neurons/metabolism, Endothelium, Vascular/metabolism, Inflammation/genetics, Membrane Proteins/genetics, Mice, Mice, Knockout, Receptors, Dopamine D1/genetics, Synaptic Transmission",
author = "Michael Fritz and Klawonn, {Anna M} and Anna Nilsson and Singh, {Anand Kumar} and Joanna Zajdel and Wilhelms, {Daniel Bj{\"o}rk} and Michael Lazarus and Andreas L{\"o}fberg and Maarit Jaarola and Kugelberg, {Unn {\"O}rtegren} and Billiar, {Timothy R} and Hackam, {David J} and Sodhi, {Chhinder P} and Breyer, {Matthew D} and Johan Jakobsson and Markus Schwaninger and G{\"u}nther Sch{\"u}tz and Parkitna, {Jan Rodriguez} and Saper, {Clifford B} and Anders Blomqvist and David Engblom",
year = "2016",
month = feb,
doi = "10.1172/JCI83844",
language = "English",
volume = "126",
pages = "695--705",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "2",

}

RIS

TY - JOUR

T1 - Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

AU - Fritz, Michael

AU - Klawonn, Anna M

AU - Nilsson, Anna

AU - Singh, Anand Kumar

AU - Zajdel, Joanna

AU - Wilhelms, Daniel Björk

AU - Lazarus, Michael

AU - Löfberg, Andreas

AU - Jaarola, Maarit

AU - Kugelberg, Unn Örtegren

AU - Billiar, Timothy R

AU - Hackam, David J

AU - Sodhi, Chhinder P

AU - Breyer, Matthew D

AU - Jakobsson, Johan

AU - Schwaninger, Markus

AU - Schütz, Günther

AU - Parkitna, Jan Rodriguez

AU - Saper, Clifford B

AU - Blomqvist, Anders

AU - Engblom, David

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

KW - Animals

KW - Brain/metabolism

KW - Brain Diseases/genetics

KW - Cell Line

KW - Cyclooxygenase 1/genetics

KW - Dinoprostone/genetics

KW - Dopaminergic Neurons/metabolism

KW - Endothelium, Vascular/metabolism

KW - Inflammation/genetics

KW - Membrane Proteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Receptors, Dopamine D1/genetics

KW - Synaptic Transmission

U2 - 10.1172/JCI83844

DO - 10.1172/JCI83844

M3 - Journal article

C2 - 26690700

VL - 126

SP - 695

EP - 705

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -

ID: 269520700