DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

Abstract

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, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMNhave not been explored. The aim of 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 functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([ 123 I]-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,GGsubjects had relatively 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 the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

Breakdown of the striatal-default mode network loop in schizophrenia

“…In return, there was a reciprocal reduction of the excitatory influence of the DMN on the striatum, indicating a breakdown of the striatal-DMN loop. A functional correlation of the striatum and the DMN has been observed in several studies (Orliac et al, 2013;Sambataro et al, 2013), which is in accordance with the basal ganglia-cortical tracts (Haber et al, 1995). The striatum is thought to play critical roles in modulating decision making (Graybiel, 2008) and working memory (together with the prefrontal cortex) (Voorn et al, 2004), as well as reward processing (Northoff and Hayes, 2011).…”

DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients

“…Another polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. 10 Interestingly, similar striatal deficits are observed during reward processing, where siblings 14 and relatives of patients 2 fail to engage the striatum in response to cues indicating a potential monetary reward. Moreover, this finding of diminished striatal flexibility mimics the effects of healthy aging on striatal activation during reward anticipation.…”

“…However, to date the functional consequences of the rs2514218 polymorphism have not yet been investigated. Other SNPs within the dopamine D2 receptor gene (DRD2), such as rs1076560, 10 have been linked to striatal function, but show no association with schizophrenia.…”

Superiority illusion arises from resting-state brain networks modulated by dopamine

“…The administration of D 2 agonists suppresses activity in the prefrontal cortex during cognitive processing (24), and the D 2 receptor genotype modulates FC strength within the default mode network and the striatum (25). Taken together, these findings suggest a possible impact of striatal dopaminergic states on resting-state fronto-striatal connectivity.…”