Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks

Although we understand how serotonin receptors function at the single-cell level, what role different serotonin receptors play in regulating brain-wide activity and, in turn, human behavior, remains unknown. Here, we developed transcriptomic-neuroimaging mapping to characterize brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics-functional magnetic resonance imaging (MRI) and pharmacology in mice, we show that activation of dorsal raphe serotonin neurons differentially modulates the amplitude and functional connectivity of different SRNs, showing that receptors' spatial distributions can confer specificity not only at the local, but also at the brain-wide, network level. In humans, using resting-state functional MRI, SRNs replicate established divisions of serotonin effects on impulsivity and negative biases. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviorally distinct modes of serotonin regulation. This suggests that serotonin neurons may regulate multiple aspects of human behavior via modulation of large-scale receptor networks.

Automated summary

In this study, the authors investigated the role of different serotonin receptors in regulating brain-wide activity and human behavior. They found that activation of specific serotonin neurons in mice modulated the amplitude and functional connectivity of different serotonin receptor networks. In humans, resting-state functional MRI also showed similar effects of serotonin receptors on impulsivity and negative biases. These findings suggest that heterogeneous distributions of serotonin receptor types in the brain may underlie behaviorally distinct modes of serotonin regulation.