Serotonin is often referred to as the “happiness molecule.” It plays a critical role in affecting mood levels and is also a neurotransmitter that sends signals within the brain and the body.

Researchers have generally thought that the chemical plays a global role in modulating brain states by acting over a longer timescale than dopamine, which signals reward but operates on a much shorter timeframe.

Now, a Dartmouth study published in The Journal of Neuroscience reports that serotonin increases in anticipation of a reward and scales with the value of that reward.

For decades, prior research has looked at the release of dopamine levels in encoding the value of rewards at a subsecond timescale using a technique that enabled scientists to monitor it throughout different areas in the mouse brain.

Techniques for monitoring serotonin at this timescale did not previously exist, leaving many unknowns about when serotonin is released in the brain because of its widespread projections. Serotonin is an extraordinarily complex system, with the cells located in one small region of the brain, which then send their messages to pretty much every other area of the brain.

There are 14 serotonin receptors, which are like 14 different locks and the key, serotonin, can fit into any one of those locks, unlocking a different message depending on the door. This explains why past studies have focused on targeting those receptors before it was possible to examine serotonin itself.

“In this research we used a new biosensor called GRAB-serotonin, for short, that could, for the first time, measure the molecule by ‘grabbing’ serotonin released in the brain, while the mouse was running around receiving a tasty treat,” says senior author Kate Nautiyal, an assistant professor of psychological and brain sciences.

Using a technique called fiber photometry, light can be used to trigger and then measure fluorescence fluctuations from a biosensor like GRAB, whenever serotonin is detected. The team was able to study the release of serotonin in mice while they received rewards, which in this case were varied concentrations of evaporated milk, which mice love. The researchers were then able to look at how serotonin levels changed depending on how good the reward was.

“We had a pretty good understanding that if you alter serotonin signaling by targeting receptors or manipulating reuptake such as with selective serotonin reuptake inhibitors, which are used in antidepressants, you get these broad impacts on mood and can change the way that animals or individuals seem to regulate behavior,” says co-author Mitchell Spring, a postdoctoral researcher who worked on this project in the Nautiyal Lab, a behavioral neuroscience lab in the Department of Psychological and Brain Sciences.

The results showed that consumption of higher concentrations of the reward were associated with greater serotonin release. When the mice were thirsty and were given water, there was a big serotonin signal, and when they were satiated with a good reward and were full, the serotonin signal was not as strong.

The findings also showed that if mice are given a cue that predicts the reward, serotonin levels rise during the cue, or anticipation, of the reward.

“We found that you can modulate the serotonin signal with the subjective value of the reward,” says Nautiyal. “Our results tell us that serotonin is really a signal in the brain monitoring how good a reward is.”

In measuring the release of serotonin, the team focused on one brain region, the dorsomedial striatum, which has previously been associated very strongly with dopamine, decision-making, and impulsivity.

The researchers say that selective serotonin reuptake inhibitors are widely prescribed and generally effective but we don’t fully understand how they work or what serotonin is doing to address the behaviors that these antidepressants are treating.

“A better understanding of how serotonin is operating at baseline or in healthy individuals during a positive experience could be used to develop more targeted treatments for psychiatric disorders like depression and addiction,” says Nautiyal.