Elsevier

Neuroscience

Volume 164, Issue 1, 24 November 2009, Pages 131-140
Neuroscience

Cognitive and Affective Function
Research Paper
Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms

https://doi.org/10.1016/j.neuroscience.2009.04.048Get rights and content

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.

Section snippets

Sample

The sample is the same as that reported in Frank et al. (2007a). There were 69 healthy participants (30 females, 39 males), between the ages of 18 and 35 (M=21). The majority of participants were white, with three participants categorizing themselves as “more than one race.” We were unable to obtain genotypes for one subject for rs2283265/rs1076560, and two subjects for rs12364283.

All SNPs were in Hardy Weinberg equilibrium (P's>0.2). The minor allele frequencies were as follows: rs12364283:

Results

There were no effects of any SNP on overall accuracy during the training phase (P's>0.1). The following analysis focuses on test phase reward and avoidance accuracy, as indicators of whether positive or negative aspects of stimuli drive their choices (Frank et al 2004, Frank et al 2005, Frank et al 2007a, Klein et al 2007).

Discussion

Taken together the above findings suggest multiple functional effects of DRD2 genes on brain D2 receptor function, which in turn contributes to probabilistic avoidance (Table 1). First, we find that the previously reported gene–dose effects of the C957T polymorphism (Frank et al., 2007a) continued to hold even when controlling for other DRD2 SNPs. These results imply a functional effect of C957T, consistent with observations that this SNP influences postsynaptic striatal D2 receptor density (

Conclusion

In sum, we show multiple genetic mechanisms associated with probabilistic avoidance learning, all linked to factors controlling striatal D2 receptor function. These effects contrast with those of other DA-related genes, such as COMT and DARPP-32 which affect other aspects of reinforcement learning. This specificity therefore supports a role for striatal D2 receptors in NoGo learning. It remains to be seen whether these genetic mechanisms generalize to other cognitive functions thought to depend

Acknowledgments

We thank Marilee Morgan and Melynda Byers for help with DNA analysis. This research was supported by NIMH grant R01 MH080066-01.

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