DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding

The default mode network (DMN) comprises a set of brain regions with ‘‘increased’’ activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560G> T) shifts splicing of the 2D2 isoforms,D2 short andD2long,andhasbeenassociatedwith striatalDAsignaling as well as with cognitive processing. However, the effectsof this polymorphismonDMNhavenotbeenexplored.Theaimof this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functionalmagnetic resonanceimaging during a working memory task and 123 55 I-Fluoropropyl-2- beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within theanteriorDMNIC,GGsubjectshadrelatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within theDMN.These results suggest that genetically determined D2 receptor signaling is associated withDMNconnectivity and that these changes are correlated with striatal function and presynaptic DA signaling.