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

Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated. Specifically, the molecular substrates of resting-state functional connectivity (rs-FC) remain poorly understood. The aim of this study was elucidating interactions between dopamine D2 receptors (D2R) and serotonin transporter (SERT) availabilities in the striatum (CPu) and medial prefrontal cortex (mPFC), two of the main dopaminergic and serotonergic projection areas, and the default-mode network. Additionally, we delineated its interaction with two other prominent resting-state networks (RSNs), the salience network (SN) and the sensorimotor network (SMN). To this extent, we performed simultaneous PET/fMRI scans in a total of 59 healthy rats using [¹¹C]raclopride and [¹¹C]DASB, two tracers used to image quantify D2R and SERT respectively. Edge, node and network-level rs-FC metrics were calculated for each subject and potential correlations with binding potentials (BP_ND) in the CPu and mPFC were evaluated. We found widespread negative associations between CPu D2R availability and all the RSNs investigated, consistent with the postulated role of the indirect basal ganglia pathway. Correlations between D2Rs in the mPFC were weaker and largely restricted to DMN connectivity. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between and within the SN, SMN and the posterior DMN, underlining the complex role of serotonergic neurotransmission in this region. Here we show direct relationships between rs-FC and molecular properties of the brain as assessed by simultaneous PET/fMRI in healthy rodents. The findings in the present study contribute to the basic understanding of rs-FC by revealing associations between inter-subject variances of rs-FC and receptor and transporter availabilities. Additionally, since current therapeutic strategies typically target neurotransmitter systems with the aim of normalizing brain function, delineating associations between molecular and network-level brain properties is essential and may enhance the understanding of neuropathologies and support future drug development.