TY - JOUR

T1 - Motivational valence is determined by striatal melanocortin 4 receptors

AU - Klawonn, Anna Mathia

AU - Fritz, Michael

AU - Nilsson, Anna

AU - Bonaventura, Jordi

AU - Shionoya, Kiseko

AU - Mirrasekhian, Elahe

AU - Karlsson, Urban

AU - Jaarola, Maarit

AU - Granseth, Björn

AU - Blomqvist, Anders

AU - Michaelides, Michael

AU - Engblom, David

PY - 2018/7/2

Y1 - 2018/7/2

N2 - 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.

AB - 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.

KW - Animals

KW - Avoidance Learning/physiology

KW - Behavior, Animal/physiology

KW - Benzazepines/administration & dosage

KW - Corpus Striatum/drug effects

KW - Dopamine/physiology

KW - Dopamine Antagonists/administration & dosage

KW - Female

KW - Male

KW - Mice

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Motivation/physiology

KW - Pro-Opiomelanocortin/physiology

KW - Receptor, Melanocortin, Type 4/deficiency

KW - Receptors, Dopamine D1/antagonists & inhibitors

KW - Reward

U2 - 10.1172/JCI97854

DO - 10.1172/JCI97854

M3 - Journal article

C2 - 29911992

VL - 128

SP - 3160

EP - 3170

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -