DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance

Abstract

Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13-15 years) and BrainChild (n∼300, age 6-27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.

Figure 1

The estimated perceived competence measured by the intrinsic motivation inventory is shown on the x-axis in relation to actual improvements in working memory of training. Data points and line fittings are illustrated according to rs1800497 genotypes. This figure is adapted for purposes of this paper based on data from a sample presented in Söderqvist et al (2013).

Figure 2

(a) Sagittal slice indicating caudate region of interest (ROI) in red and VS ROI in green (x=−16); (b, c) individuals with lower VS/caudate blood oxygenation level dependent (BOLD) defined through a median split of BOLD responses during reward anticipation make significantly more errors on a WM test relative to individuals with high VS/caudate BOLD.

Figure 3

(a) rs1800497 × ventral striatum (VS) blood oxygenation level dependent (BOLD) interaction suggesting that individuals carrying the A-allele make more errors on a working memory (WM) (r=−0.24, p<0.0001, r²=5.6%) when they have reduced VS BOLD during reward anticipation. The negative correlation was not significant amongst GG-homozygotes (r=−0.04, p=0.27, r²=0.2%). Residuals of WM errors after controlling for centre and gender are shown. (b) Depiction of main effects and interactions from the model rs1800497+striatal BOLD+rs1800497 × striatal BOLD=WM (controlling for centre and gender) based on the IMAGEN sample. The non-significant effects of rs1800497 on BOLD responses are based on the individual analyses. The figure shows significant main effects of rs1800497 on WM, main effects of caudate and VS BOLD on WM as well as interactions between rs1800497 and BOLD responses on WM.