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Motivational valence is determined by striatal melanocortin 4 receptors
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
NIDA, MD USA.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed) Published
Abstract [en]

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. opioid receptorinduced 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.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC , 2018. Vol. 128, no 7, p. 3160-3170
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Neurosciences
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URN: urn:nbn:se:liu:diva-149861DOI: 10.1172/JCI97854ISI: 000437234600044PubMedID: 29911992OAI: oai:DiVA.org:liu-149861DiVA, id: diva2:1236437
Note

Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland; National Institute on Drug Abuse Intramural Research Program [ZIA000069]; Lars Hiertas Minne Foundation

Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2018-08-20

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Klawonn, AnnaFritz, MichaelNilsson, AnnaShionoya, KisekoMirrasekhian, ElaheKarlsson, UrbanJaarola, MaaritGranseth, BjörnBlomqvist, AndersEngblom, David

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Klawonn, AnnaFritz, MichaelNilsson, AnnaShionoya, KisekoMirrasekhian, ElaheKarlsson, UrbanJaarola, MaaritGranseth, BjörnBlomqvist, AndersEngblom, David
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