Dissecting the Functional Organization of the Serotonergic System at Whole-Brain Scale in C. elegans

Serotonin signaling is evolutionarily ancient and controls many aspects of behavior. The principles by which serotonin acts on its diverse types of receptors to modulate neural circuit activity and resultant behavior is poorly understood. Here, we examine how serotonin released from a food-responsive neuron in C. elegans alters neural activity at whole-brain scale to induce adaptive behaviors, such slow locomotion and increased pharyngeal pumping. A comprehensive in vivo genetic analysis of the six C. elegans serotonin receptors identifies three core serotonin receptors that sense serotonin release with different temporal kinetics to induce slow locomotion upon serotonin release. By expressing stereotypical combinations of fluorophores across all the neurons, we map out the exact sites of serotonin receptor expression in the connectome. Receptor swap experiments show that the behavioral responses to serotonin is attributable to the unique sites where these receptors are expressed. Brain-wide calcium imaging during food-triggered serotonin release reveals widespread neural dynamics that are significantly correlated moment-to-moment with the activity of the serotonergic neuron, which impacts different behavioral networks in different ways. The exact sites of receptor expression partially predict their correlation strength with the serotonergic neuron as it releases serotonin to the neuropil. In addition, we observe that serotonin-associated brain dynamics extend much more broadly than predicted from the structural connectome. These results provide a global view of how serotonin acts on specific receptors at defined sites in a connectome to modulate circuits and behavior in response to changes in the sensory environment.