New Pathway Involved in Reward and Aversion Uncovered

Researchers in Japan have reported new insights into the opposing actions of serotonin-producing nerve fibers in mice that could lead to new treatments for addiction and major depression. Specifically, the team from Hokkaido University and Kyoto University identified a nerve pathway that originates in a bundle of brain stem nerve fibers called the median raphe nucleus and participates in the processing of rewarding and distressing stimuli.

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.

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 the nearby dorsal raphe nucleus, even though it also is a source of serotonergic nerve fibers.

The team 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 an unpleasant stimulus—such as pinching a mouse’s tail—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.

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 interpeduncular 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. “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,” adds Ohmura.

The findings were published recently in Nature Communications.