Reward and Unease Are Closely Linked in the Brain

Summary: Researchers say melanocortin 4 receptors may play a role in unease and reward. The study reports dopamine levels fell in the reward system of mice when the animal experienced something unpleasant. However, in mice lacking the melanocortin 4 receptor, dopamine levels increased slightly following a negative experience.

Source: Linkoping University.

The brains of both humans and other animals have circuits that connect powerful impressions from the senses to positive or negative feelings – a function that is necessary for survival. These circuits drive the organism to seek things that increases the probability of survival and reproduction, such as food and sex, since these produce pleasure. Along the same line, the evaluation helps animals to avoid harmful things and situations, linked to feelings of unease and depression. The signal circuits in the brain that regulate our experience of positive and negative are also activated by disease. During long-term disease, such as chronic inflammatory diseases, cancer and depression, the system can cause huge suffering by negatively affecting motivation and mood.

The research group led by David Engblom at Linköping University has previously discovered a mechanism that explains why inflammatory diseases lead to unease and depressive symptoms. In the new study, the researchers were interested in a specific type of receptor, the melanocortin 4 receptor, found on certain nerve cells. They studied mice that lacked melanocortin 4 receptors and examined how the animals reacted to inflammation.

“Normal mice avoid an environment that they associate with becoming sick, if they can choose between it and another place. Mice that lack the melanocortin 4 receptor behave in the opposite manner, and are attracted to such environments, as if they liked the inflammation”, says David Engblom, associate professor at the Department of Clinical and Experimental Medicine and head of the study.

Other things that normal mice and people experience as uncomfortable, such as nausea, also caused the mice to seek out an environment that they associated with such experiences. The behaviour of the animals surprised the researchers.

“We have previously seen that removal of specific receptors in the brain can make animals indifferent to inflammation. But I’ve never before seen a switch from being associated with punishment to reward”, says David Engblom.

One of the key components of the reward system is the signal substance dopamine, which acts as a chemical messenger between nerve cells. Dopamine stimulates motivation and causes animals and humans to exert themselves to achieve anything that is experienced as rewarding. When the researchers examined the dopamine-based signalling in the brain, they saw that the dopamine level in normal mice fell in the reward centre of the brain when the animals experienced something unpleasant. In contrast, it increased slightly in the mice that lacked melanocortin 4 receptors.

the striatum in the brain
When the researchers examined the dopamine-based signalling in the brain, they saw that the dopamine level in normal mice fell in the reward centre of the brain when the animals experienced something unpleasant. In contrast, it increased slightly in the mice that lacked melanocortin 4 receptors. image is in the public domain.

“It seems that this receptor in some way prevents danger signals from activating the reward system. If the receptor is missing, the danger signals will gain access to the reward system and activate it. This means that mice that lack the receptor will seek out things that are associated with danger or discomfort”, says David Engblom.

It is too early to say whether the mechanism acts in the same way in humans. During long-term disease, patients often feel bad due to a combination of pain, nausea and inflammation. This means that it may be interesting to study the melanocortin 4 receptor in more depth, since it seems to be involved in many types of unease and discomfort.

About this neuroscience research article

Funding: Researchers Anna Klawonn and Michael Fritz have played a central roll in the study, which has been conducted in collaboration with researchers at the National Institute of Drug Abuse in the US. The research has received funding from bodies that include the European Research Council (ERC), the Swedish Research Council, the Knut and Alice Wallenberg Foundation and the Swedish Brain Foundation.

Source: Karin Söderlund Leifler – Linkoping University
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Open access research for “Motivational valence is determined by striatal melanocortin 4 receptors” by Anna Mathia Klawonn, Michael Fritz, Anna Nilsson, Jordi Bonaventura, Kiseko Shionoya, Elahe Mirrasekhian, Urban Karlsson, Maarit Jaarola, Björn Granseth, Anders Blomqvist, Michael Michaelides, and David Engblom in Journal of Clinical Investigation. Published June 18 2028.

Cite This Article

[cbtabs][cbtab title=”MLA”]Linkoping University”Reward and Unease Are Closely Linked in the Brain.” NeuroscienceNews. NeuroscienceNews, 2 July 2028.
<>.[/cbtab][cbtab title=”APA”]Linkoping University(2028, July 2). Reward and Unease Are Closely Linked in the Brain. NeuroscienceNews. Retrieved July 2, 2028 from[/cbtab][cbtab title=”Chicago”]Linkoping University”Reward and Unease Are Closely Linked in the Brain.” (accessed July 2, 2028).[/cbtab][/cbtabs]


Motivational valence is determined by striatal melanocortin 4 receptorss

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.

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