Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms

Abstract

Individuals differ in their tendencies to seek positive decision outcomes or to avoid negative ones. At the neurobiological level, our model suggests that phasic changes in dopamine support learning to reinforce good decisions via striatal D1 receptors, and to avoid maladaptive choices via striatal D2 receptors. Accordingly, in a previous study individual differences in positive and negative learning were strongly modulated by two genetic polymorphisms factors related to striatal D1 and D2 function, respectively. Nevertheless, whereas the role for dopamine in positive learning is relatively well accepted, that in learning to avoid negative outcomes is more controversial. Here we further explore D2-receptor-related genetic contributions to probabilistic avoidance in humans, in light of recent data showing that particular DRD2 polymorphisms are associated with functional modulation of receptor expression [Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee M-LT, Xiao T, Papp A, Wang D, Sadée W (2007) Polymorphisms in human dopamine d2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A 104(51):20552-20557]. We find that a promoter polymorphism rs12364283 associated with transcription and D2 receptor density was strongly and selectively predictive of avoidance-based decisions. Two further polymorphisms (rs2283265 and rs1076560) associated with relatively reduced presynaptic relative to postsynaptic D2 receptor expression were predictive of relative impairments in negative compared to positive decisions. These previously undocumented effects of DRD2 polymorphisms were largely independent of those we reported previously for the C957T polymorphism (rs6277) associated with striatal D2 density. In contrast, effects of the commonly studied Taq1A polymorphism on reinforcement-based decisions were due to indirect association with C957T. Taken together these findings suggest multiple D2-dependent genetic mechanisms contributing to avoidance. We discuss these effects in the context of neurocomputational models of reinforcement leaning in the basal ganglia.

Figure 1

a) Probabilistic selection reinforcement learning task. During training, participants select among each stimulus pair. Probabilities of receiving positive/negative feedback for each stimulus are indicated in parentheses. In the test phase, all combinations of stimuli are presented without feedback. “Go learning” is indexed by reliable choice of the most positive stimulus A in these novel pairs, whereas “NoGo learning” is indexed by reliable avoidance of the most negative stimulus B. b) Striatal Go and NoGo activation states when presented with input stimuli A and B respectively. Simulated Parkinson’s (Sim PD) was implemented by reducing striatal DA levels, whereas medication (Sim DA Meds) was simulated by increasing DA levels and partially shunting the effects of DA dips during negative feedback. c) Behavioral findings in PD patients on/off medication supporting model predictions (Frank et al., 2004). d) Replication in another group of patients, where here the most prominent effects were observed in the NoGo learning condition (Frank et al., 2007b). e), f) Individual differences in Go/NoGo learning in college students are predicted by genes controlling striatal D1/D2 function (Frank et al., 2007a).

Figure 2

Gene dose effects. a) Monotonic effects of number of T alleles in the DRD2 gene, showing increased striatal D2 receptor density (Adapted by permission from Macmillan Publishers Ltd: Molecular Psychiatry, (Hirvonen et al., 2005), copyright 2005). b) DRD2 c957T gene dose effect on probabilistic avoidance learning (Frank et al, 2007, PNAS). Individuals with more T alleles performed better, and were relatively faster, at avoid-B test pairs. RT’s are assessed on correct trials and slowing is measured by subtracting choose-A from avoid-B RT’s. Error bars reflect standard error.

Figure 3

DRD2 effects on accuracy in choose-A (approach) and avoid-B (avoidance) conditions. a) Taq1A SNP, showing relatively impaired avoidance in A1+ carriers. However this effect appears to be due to indirect linkage with C957T (see text). b Promoter SNP 2 from Zhang et al, affecting D2 receptor mRNA transcription, selectively and substantially impacted avoidance learning. c) SNPs 17/19 from Zhang et al, affecting relative presynaptic autoreceptor vs postsynaptic D2 receptor expression, impacted relative reward to avoidance learning. d) Interactions between SNPs 17/19 and C957T. Carriers of the major rs2283265/rs1076560 GG genotype who were also C957T TT carriers showed relative better avoidance learning, whereas carriers of the minor rs2283265/rs1076560 allele who also carried a C957T C allele showed relatively impaired avoidance but better reward learning. The intermediate group showed no learning bias.

Figure 4

Gene dose effects of C957T on relative avoidance in a) all participants, b) carriers of the major T/T genotype of rs12364283, and c) carriers of the major G/G genotype of SNPS 17/19.

Figure 5

Gene-gene interactions on performance in the Avoid-B test condition. Although SNPs 17/19 and C957T were all predictive of avoidance learning, the presence of the major GG genotype in SNPs 17/19 was protective against the detrimental effects of the C957T C/C genotype.