How serotonin, the 'feel good hormone,' impacts your entire brain

“There have been major challenges in rationally developing psychiatric drugs that target the serotonergic system. The system is wildly complex. There are many different types of serotonergic neurons with widespread projections throughout the brain and serotonin acts through many different receptors, which are often activated in concert to change the way that neural circuits work," said Steve Flavell, associate professor at The Picower Institute and senior author of the study.

The mapping of a worm's brain

C. elegans’ nervous system has 302 neurons with known connectivity, while a human brain has billions. These worms have six serotonin receptors, while humans have 14. Their serotonergic system is important for their behavior and has some of the same receptor types as humans do. Its organization resembles that of mammals, revealed the study. In order to track these neural activities, the team also developed a new imaging technology that could map the activity across the worm’s brain.

Flavell mentions in the press release that in his previously published studies, he was able to discover that the worms use serotonin to slow down to savor a meal when it senses that the worm has ingested bacteria. The team was able to trace the source of the signal to a neuron called NSM. In the new study, the team used these observations to study which serotonin receptor on which neuron plays a role in those effects.

What the team learned

The team observed two things, Flavell explains. The first being that the team identified three receptors that primarily drove the slowing behavior in worms. The second was that the other three receptors "interacted" with the receptors that drove the slowing pattern and modulated how they function. The team concluded that these complex interactions between serotonin receptors that influence our behavior are a key factor in the psychiatric drugs that target these receptors.

Using their imaging technology, the team made a brain-wide map of serotonin receptors in C. elegans, which revealed widespread serotonin-linked brain dynamics spanning many behavioral networks. Researchers found that about half of the neurons across the worm's brain changed activity when serotonin was released.

Flavell added that their research will shed light on the complexity of the effects of serotonin in brain activity and in turn help drug developers.

The study was published in the journal Cell.

Study abstract:

Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. Comprehensive genetic analyses identify three core serotonin receptors (MOD-1, SER-4, and LGC-50) that induce slow locomotion upon serotonin release and others (SER-1, SER-5, and SER-7) that interact with them to modulate this behavior. SER-4 induces behavioral responses to sudden increases in serotonin release, whereas MOD-1 induces responses to persistent release. Whole-brain imaging reveals widespread serotonin-associated brain dynamics, spanning many behavioral networks. We map all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict which neurons show serotonin-associated activity. These results reveal how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.