Good and bad feelings for brain stem serotonin

Source:

Hokkaido University

Summary:

New insights into the opposing actions of serotonin-producing nerve fibers in mice could lead to drugs for treating addictions and major depression.

A neural network involved in the processing of rewarding and upsetting stimuli and situations in mice has been discovered by scientists in Japan.

The newly discovered reward/aversion pathway, which has its beginnings in the adjacent dorsal raphe nucleus, works in opposition to a previously discovered reward/aversion pathway. The results, which were published in the journal Nature Communications by researchers from Kyoto University and Hokkaido University alongside their colleagues, may have consequences for the creation of medication to treat a variety of mental diseases, such as addiction and serious depression.

Previous research has already established that the delightful sensation related to reward is induced by stimulating serotonin-producing nerve fibers from the dorsal raphe nucleus in the brain stem of rats. However, selective serotonin reuptake inhibitors (SSRIs), antidepressant medications that raise serotonin levels in the brain, do not effectively address the depression-related loss of the ability to experience pleasure or exert unambiguous sensations of reward. This implies the existence of additional serotonin-producing neural pathways in the brain connected to experiences of reward and aversion.

Yu Ohmura, a neuropharmacologist at Hokkaido University, and Kazuki Nagayasu, a pharmacologist at Kyoto University, together with researchers from other Japanese universities, have concentrated on the median raphe nucleus to learn more about the reward and aversion neural pathways of the brain. Despite the fact that this region is a source of serotonergic nerve fibers, it has not attracted as much study attention as its neighbor in the brain stem, the dorsal raphe nucleus.

The scientists used fluorescent proteins that detect calcium ion entry, a proxy for neuronal activation in a cell-type specific way, to quantify activity of serotonin neurons in mice in response to stimulating and inhibiting the median raphe.

They discovered that unpleasant stimuli, such as squeezing a mouse's tail, enhanced calcium-dependent fluorescence in the median raphe's serotonin neurons. On the other hand, giving mice a treat like sugar decreased the median raphe serotonin fluorescence. Additionally, employing a genetic technique involving light to directly stimulate or inhibit the median raphe nucleus resulted in unpleasant or rewarding behaviors, such as the desire to avoid or remain in a chamber, depending on the type of stimulus used.

The team then performed tests to determine where the median raphe's activated serotonergic nerve fibers were conveying signals, and they discovered a crucial link with the interpenduncular nucleus of the brain stem. Additionally, they discovered serotonin receptors in this nucleus that were responsible for the unpleasant effects of middle raphe serotonergic activity.

To completely understand this route and others connected to rewarding and unpleasant feelings and behaviors, more research is required. According to Ohmura, "These new insights could help us better understand the molecular underpinnings of mental diseases where abnormal processing of rewarding and unpleasant information occurs, such as drug addiction and major depressive disorder."

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Materials provided by Hokkaido University. Note: Content may be edited for style and length.

Journal Reference:

1. Hiroyuki Kawai, Youcef Bouchekioua, Naoya Nishitani, Kazuhei Niitani, Shoma Izumi, Hinako Morishita, Chihiro Andoh, Yuma Nagai, Masashi Koda, Masako Hagiwara, Koji Toda, Hisashi Shirakawa, Kazuki Nagayasu, Yu Ohmura, Makoto Kondo, Katsuyuki Kaneda, Mitsuhiro Yoshioka, Shuji Kaneko. Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-35346-7