Researchers in Japan have identified a nerve pathway in mice involved in the processing of rewarding and distressing stimuli and situations. The pathway, originating in a bundle of brain stem nerve fibers called the median raphe nucleus, acts in opposition to a previously identified reward/aversion pathway that originates in the nearby dorsal raphe nucleus.

The study “Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion,” published in Nature Communications, could have implications for developing drug treatments for various mental disorders, including addictions and major depression.

Previous studies had already revealed that activating serotonin-producing nerve fibers from the dorsal raphe nucleus in the brain stem of mice leads to the pleasurable feeling associated with reward. However, selective serotonin reuptake inhibitors (SSRIs), antidepressant drugs that increase serotonin levels in the brain, fail to exert clear feelings of reward and to treat the loss of ability to feel pleasure associated with depression. This suggests that there are other serotonin-producing nerve pathways in the brain associated with the feelings of reward and aversion.

Focused attention on the median raphe nucleus

To further study the reward and aversion nerve pathways of the brain, Hokkaido University neuropharmacologist Yu Ohmura and Kyoto University pharmacologist Kazuki Nagayasu, together with colleagues at several universities in Japan, focused their attention on the median raphe nucleus. This region has not received as much research attention as its brain stem neighbor, the dorsal raphe nucleus, even though it also is a source of serotonergic nerve fibers.

The scientists conducted a wide variety of tests to measure activity of serotonin neurons in mice, in response to stimulating and inhibiting the median raphe, by using fluorescent proteins that detect entry of calcium ions, a proxy of neuronal activation in a cell-type specific manner.

They found that, for example, pinching a mouse’s tail—an unpleasant stimulus—increased calcium-dependent fluorescence in the serotonin neurons of the median raphe. Giving mice a treat such as sugar, on the other hand, reduced median raphe serotonin fluorescence. Also, directly stimulating or inhibiting the median raphe nucleus, using a genetic technique involving light, led to aversive or reward-seeking behaviors, such as avoiding or wanting to stay in a chamber—depending on the type of stimulus applied.

“Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli,” write the investigators.

“Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity.

“Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.”

An illustration of the facial expression changes in mice following stimulation and inhibition of the median raphe nucleus. [Yu Ohmura/Hokkaido University]
The team also conducted tests to discover where the switched-on serotonergic nerve fibers of the median raphe were sending signals to and found an important connection with the brain stem’s interpenduncular nucleus. They also identified serotonin receptors within this nucleus that were involved in the aversive properties associated with median raphe serotonergic activity.

Further research is needed to fully elucidate this pathway and others related to rewarding and aversive feelings and behaviors, according to the researchers.

“These new insights could lead to a better understanding of the biological basis of mental disorders where aberrant processing of rewards and aversive information occur, such as in drug addiction and major depressive disorder,” says Ohmura.

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