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 brainregions with ‘‘increased’’ activity during rest relative to cognitiveprocessing. Activity in the DMN is associated with functionalconnections with the striatum and dopamine (DA)levels in this brain region. A functional single-nucleotide polymorphismwithin the dopamine D2 receptor gene (DRD2,rs1076560G> T) shifts splicing of the 2D2 isoforms,D2 shortandD2long,andhasbeenassociatedwith striatalDAsignalingas well as with cognitive processing. However, the effectsof thispolymorphismonDMNhavenotbeenexplored.Theaimof thisstudy was to evaluate the effects of rs1076560 on DMN andstriatal connectivity and on their relationship with striatalDA signaling. Twenty-eight subjects genotyped forrs1076560 underwent functionalmagnetic resonanceimagingduring a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan SinglePhoton Emission Computed Tomography ([123I]-FP-CITSPECT) imaging (a measure of dopamine transporter[DAT] binding). Spatial group-independent component (IC)analysis was used to identify DMN and striatal ICs. WithintheanteriorDMNIC,GGsubjectshadrelatively greater connectivityin medial prefrontal cortex (MPFC), which was directlycorrelated with striatal DAT binding. Within theposterior DMN IC, GG subjects had reduced connectivityin posterior cingulate relative to T carriers. Additionally,rs1076560 genotype predicted connectivity differenceswithin a striatal network, and these changes were correlatedwith connectivity in MPFC and posterior cingulate withintheDMN.These results suggest that genetically determinedD2 receptor signaling is associated withDMNconnectivityand that these changes are correlated with striatal functionand presynaptic DA signaling.