Striatal and prefrontal D2R and SERT distributions contrastingly correlate with default-mode connectivity

The molecular substrate of resting-state functional connectivity (rs-FC) remains poorly understood. We aimed to elucidate interactions of dopamine D2 receptor (D2R) and serotonin transporter (SERT) availabilities in main dopaminergic and serotonergic projection areas with the default-mode network (DMN) and two other resting-state networks (RSNs), the salience (SN) and sensorimotor networks (SMN). We performed simultaneous PET/fMRI scans in rats using [ 11 C]raclopride and [ 11 C]DASB to image D2R and SERT distributions, showing for the first time direct relationships between rs-FC and molecular properties of the rodent brain. We found negative associations between CPu D2R availability and all RSNs investigated. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between the other networks, underlining serotonin’s intricate role in this region. By further elucidating the link between molecular brain properties and its network-level function, our data support future diagnostic and therapeutic strategies. Teaser Simultaneous PET/fMRI indicates direct associations between monoaminergic neurotransmission and brain functional networks.