Mood Regulation Subject to Mixed Serotonin Signals

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What’s sauce for the goose is sauce for the gander, unless the sauce is an antidepressant meant to boost serotonin levels in the brain. That’s one way to understand a new study that indicates different serotonin-producing brain regions can have opposing effects on emotional behaviors. According to this study, two brain regions in particular, the dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN), appear to have a yin-and-yang relationship when it comes to mood regulation.

Specifically, one region’s serotonergic activity can offset the other region’s serotonergic activity. This finding, which emerged from pharmacogenetic research conducted at Columbia University, provides new insights into the development of mood disorders and may aid in designing improved therapies.

The Columbia University research effort was led by Mark S. Ansorge, Ph.D. “Our study breaks with the simplistic view that 'more is good and less is bad,' when it comes to serotonin for mood regulation,” he said. “Rather, it tells us that a more nuanced view is necessary.”

The study’s details appeared November 19 in Cell Reports, in an article entitled, “Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors.” The article noted that even though serotonin signaling has a well-established role in mood regulation, the causal relationships between serotonergic neuronal activity and behavior remain unclear.

To explore these relationships, Dr. Ansorge's team used a technique called pharmacogenetics to control the activity of serotonergic neurons in the DRN and MRN in both normal mice and in a mouse model of depression- and anxiety-like behavior. (The model was created by giving mice the drug fluoxetine shortly after birth, which produces long-lasting behavioral changes.)

“[Selectively] increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures,” wrote the authors of the Cell Reports article. “In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition.”

In addition, the researchers identified opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior. This observation, the researchers surmised, could mean that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior.

“We find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function,” the authors concluded.

“Going into the study, our hypothesis was that reduced activity of serotonergic neurons is what drives these mood behaviors,” said Dr. Ansorge. “But what we found was more complicated.” Essentially, Dr. Ansorge and colleagues found that it is an imbalance between DRN and MRN activity that leads to depression-like behavior.

“This new understanding of the raphe nuclei should help us better understand why certain medications are effective in treating depression and anxiety, and aid in designing new drugs,” Dr. Ansorge added. “In the future, it may be possible to find treatments that selectively target the DRN or the MRN, or that correct any imbalance between the two.”

The study also demonstrated, in the experiments using the fluoxetine-treated mice, that inhibition of serotonin reuptake early in life leads to long-lasting imbalances between the DRN and MRN. “This raises possible concerns about exposure to serotonin-specific reuptake inhibitors during gestation,” noted Dr. Ansorge. “SSRIs cross the blood-brain barrier as well as the placenta, and bind maternal and fetal serotonin transporters alike. It's too early to say whether this has any effect on behavior in humans, but it's certainly something worth looking into.”