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Motivational valence is determined by striatal melanocortin 4 receptors
Anna Mathia Klawonn, … , Michael Michaelides, David Engblom
Anna Mathia Klawonn, … , Michael Michaelides, David Engblom
Published June 18, 2018
Citation Information: J Clin Invest. 2018;128(7):3160-3170. https://doi.org/10.1172/JCI97854.
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Research Article Inflammation Neuroscience

Motivational valence is determined by striatal melanocortin 4 receptors

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Abstract

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor–induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor–expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Authors

Anna Mathia Klawonn, Michael Fritz, Anna Nilsson, Jordi Bonaventura, Kiseko Shionoya, Elahe Mirrasekhian, Urban Karlsson, Maarit Jaarola, Björn Granseth, Anders Blomqvist, Michael Michaelides, David Engblom

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Figure 7

POMC neurons projecting to the ventral striatum activate striatal neurons in a MC4R-dependent manner.

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POMC neurons projecting to the ventral striatum activate striatal neuron...
(A) Cell-attached recordings from the striatum showed that optogenetic activation of POMC projection neurons increased cell firing in a glutamate receptor– and MC4R-dependent manner (n =4 out of 18 Chr2: POMCCre). Representative traces (15 seconds) from the end of a recording, where most action potentials occurred. (B) Timeline of the experiment using DREAMM and an image of [18F]FDG uptake in the brain. (C–E) DREAMM using [18F]FDG PET after CNO-induced activation of POMC cells projecting to the ventral striatum. hM3Dq was expressed in the same way as in Figure 6D. Clear activation (orange labeling; P < 0.01) was seen in the striatum on the same side as the viral injection (n = 7 POMCCre) as well as in both ventral and dorsal striatum and the PI of the contralateral side. Voxel statistics analysis in MATLAB and SPM; clusters of more than 100 voxels, P < 0.01 (C and D). Results are displayed as mean ± SEM. *P < 0.05; **P <0.01; ***P < 0.001, ANOVA followed by Bonferroni’s post hoc test (A); Student’s t test (E).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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