Serotonin regulation of behaviour 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 behaviour, remains unknown. Here, we developed transcriptomic-neuroimaging mapping to characterise brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics-fMRI 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 fMRI, different sets of SRNs are linked to different behavioural phenotypes. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviourally-distinct modes of serotonin regulation. This suggests that dorsal raphe serotonin neurons may regulate multiple aspects of human behaviour via modulation of large-scale receptor networks.