Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Inflammation Neuroscience Article has an altmetric score of 189

Motivational valence is determined by striatal melanocortin 4 receptors

  • Text
  • PDF
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

×

Figure 5

MC4Rs on striatal neurons expressing the D1R are critical for aversion.

Options: View larger image (or click on image) Download as PowerPoint
MC4Rs on striatal neurons expressing the D1R are critical for aversion.
...
(A and B) Micrographs from the striatum (A, CPu; B, NAc) showing MC4R expression (eGFP) in green and D1R expression (tdTomato) in red. (C) MC4R-KO mice with rescue of MC4R expression selectively in D1R-expressing cells responded with place aversion to LPS (n = 5 WT; n = 11 KO; n = 7 MC4R-D1-rescue). resc, rescue. (D) Rescue of MC4Rs selectively on dopamine cells did not restore aversion (n = 5 WT; n = 4 KO; n = 6 MC4R-DAT-rescue). (E and F) Rescue of MC4Rs on D1R cells normalized the aversive responses of MC4R-KO mice to the κ receptor agonist U50488 (E, n = 8 WT; n = 10 KO; n = 7 MC4R-D1-rescue) and to inflammatory pain (F, n= 7 WT; n = 8 KO; n = 6 MC4R-D1-rescue) (F). (G) Expression of Cre in the striatum was induced by a local injection of a viral vector together with a Cre-dependent eGFP-expressing viral vector. LV, lateral ventricle. (H) MC4R-KO mice with rescue of MC4R expression in the striatum displayed intact aversive responses to LPS (n = 6 WT AAV5-Cre; n = 9 KO AAV5-GFP; n = 5 MC4R-rescue in KO with AAV5-Cre). Results are displayed as mean ± SEM. *P < 0.05; **P < 0.01, ANOVA followed by Bonferroni’s post hoc test. Scale bar: 20 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 22 news outlets
Blogged by 2
Posted by 28 X users
On 4 Facebook pages
72 readers on Mendeley
See more details