Scientists headed by Hokkaido University neuropharmacologist Yu Ohmura, PhD, and Kyoto University pharmacologist Kazuki Nagayasu, PhD, have identified a nerve pathway involved in the processing of rewarding and distressing stimuli and situations in mice.  The new pathway, originating in a bundle of brain stem nerve fibres called the median raphe nucleus (MRN), acts in opposition to a previously identified reward/aversion pathway that originates in the nearby dorsal raphe nucleus (DRN).

The new insights into the opposing actions of serotonin-producing nerve fibres in these two regions of the brain could help point to the development of drugs for treating addictions and major depression. “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,” said Ohmura.

The scientists described the findings from their murine studies in Nature Communications, in a paper titled “Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion,” in which they reported “our findings demonstrate the opposite role of the MRN to the DRN in regulating the balance between preference and aversion, and further elucidate the serotonergic pathway and related 5-HT receptor subtypes.”

Processing reward and aversive information is essential for the survival of living organisms, the authors wrote. “Aberrant neural activity underlying this processing can cause under- and overestimation of the value of extrinsic stimuli, which are frequently seen in patients with mental disorders including drug addiction and major depression. Therefore, it is of high importance to better understand the neuronal mechanisms underlying the processing of reward and aversion.”

Previous studies had already revealed that activating serotonin-producing nerve fibres from the dorsal raphe nucleus in the brain stem of mice leads to the pleasurable feeling associated with reward. While the DRN and MRN are the main origins of serotonergic projections to the forebrain, the authors noted, the MRN has not received as much research attention as its brain stem neighbour, the DRN, even though it also is a source of serotonergic nerve fibres.“ …most studies have focused on the DRN and revealed that optogenetic activation of serotonergic neurons in the DRN is rewarding,” the team stated. 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. “These contradictory findings imply that serotonin neurons in the MRN might play an opposite role to the DRN in the processing of reward and aversive stimuli.”

To further study the reward and aversion nerve pathways of the brain, Ohmura and Nagayasu, together with colleagues at several universities in Japan, focused their attention on the median raphe nucleus. They 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 behaviours, such as avoiding or wanting to stay in a chamber—depending on the type of stimulus applied. “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,” the scientists reported.

The team also conducted tests to discover where the switched-on serotonergic nerve fibres of the median raphe were sending signals to and found an important connection with the brain stem’s interpeduncular nucleus (IPN). They also identified serotonin receptors within this nucleus that were involved in the aversive properties associated with median raphe serotonergic activity. “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.”

Their data, they stated, suggest that 5-HT receptors, including 5-HT2A receptors in the IPN, are involved in the aversive properties associated with MRN serotonergic neuron activity. “Further identification of the mechanisms underlying 5-HT2A signaling in the IPN will provide insights into a better understanding of the processing of rewards and aversive stimuli and the biological basis of mental disorders where aberrant processing of rewards and aversive information are observed, such as in drug addiction and major depressive disorder.”

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