New insights into the opposing actions of serotonin-producing nerve fibers in mice might lead to drugs to treat addictions and major depression.
Japanese scientists have identified a neural pathway involved in processing rewarding and distressing stimuli and situations in mice.
The new pathway, originating from a bundle of nerve fibers in the brainstem called the medial raphe nucleus, acts in opposition to a previously identified reward/aversion pathway that originates in the neighboring dorsal raphe nucleus. The results, published by scientists from Hokkaido University and Kyoto University with their colleagues in the journal Communication Naturemight have implications for the development of drug treatments for various mental disorders, including addictions and major depression.
Previous studies had already revealed that the activation of serotonin-producing nerve fibers from the dorsal raphe nucleus in the brainstem of mice leads to the feeling of pleasure associated with reward. However, selective serotonin reuptake inhibitors (SSRIs), antidepressants that increase serotonin levels in the brain, fail to exert clear feelings of reward and address the loss of ability to experience pleasure associated with the Depression. This suggests that there are other serotonin-producing nerve pathways in the brain associated with feelings of reward and aversion.
To further investigate the brain’s reward and aversive neural pathways, Hokkaido University neuropharmacologist Yu Ohmura and Kyoto University pharmacologist Kazuki Nagayasu, along with colleagues from several universities in Japan, have focused their attention on the nucleus of the medial raphe. This region has not received as much research attention as its brainstem neighbor, the dorsal raphe nucleus, even though it is also a source of serotonergic nerve fibers.
Scientists conducted a wide variety of tests to measure the activity of serotonin neurons in mice, in response to stimulation and inhibition of the medial raphe, using fluorescent proteins that detect the entry of calcium ions , a proxy for 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 serotonin neurons in the medial raphe. Giving the mice a treat such as sugar, on the other hand, reduced median raphe serotonin fluorescence. In addition, direct stimulation or inhibition of the medial raphe nucleus, using a genetic technique involving light, led to aversive or reward-seeking behaviors, such as avoiding or wanting to stay in a room, depending on the type of stimulus applied.
The team also performed tests to find out where activated serotonergic nerve fibers in the medial raphe were sending signals and found an important connection with the interpenduncular nucleus of the brainstem. They also identified serotonin receptors within this nucleus that were implicated in the aversive properties associated with median raphe serotonergic activity.
Further research is needed to fully elucidate this and other pathways related to gratifying and aversive feelings and behaviors. “This new knowledge might lead to a better understanding of the biological basis of mental disorders where aberrant processing of rewards and aversive information occurs, such as in substance abuse and major depressive disorder,” says Ohmura.
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