Dopamine DRD2 polymorphism alters reversal learning and associated neural activity

Abstract

In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIa polymorphism is associated with reduced expression of dopamine (DA) D(2) receptors in the striatum. Recently, it was observed that carriers of the A1 allele (A1+ subjects) showed impaired learning from negative feedback in a reinforcement learning task. Here, using functional MRI (fMRI), we investigated carriers and noncarriers of the A1 allele while they performed a probabilistic reversal learning task. A1+ subjects showed subtle deficits in reversal learning. In particular, these deficits consisted of an impairment in sustaining the newly rewarded response after a reversal and in a generally decreased tendency to stick with a rewarded response. Both genetic groups showed increased fMRI signal in response to negative feedback in the rostral cingulate zone (RCZ) and anterior insula. Negative feedback that incurred a change in behavior additionally engaged the ventral striatum and a region of the midbrain consistent with the location of dopaminergic cell groups. The response of the RCZ to negative feedback increased as a function of preceding negative feedback. However, this graded response was not observed in the A1+ group. Furthermore, the A1+ group also showed diminished recruitment of the right ventral striatum and the right lateral orbitofrontal cortex (lOFC) during reversals. Together, these results suggest that a genetically driven reduction in DA D(2) receptors leads to deficient feedback integration in RCZ. This, in turn, was accompanied by impaired recruitment of the ventral striatum and the right lOFC during reversals, which might explain the behavioral differences between the genetic groups.

Figure 1.

A, Sequence of events within a trial of the probabilistic reversal learning task. After selection of one of the two stimuli, the choice was visualized to the subject by depression and darkening of the respective button on the screen. This was followed after 100 ms by positive or negative feedback, according to the task schedule. B, Example of a sequence of trials and the categorization of the trials according to the subject's response and the feedback obtained.

Figure 2.

Persistence of behavioral adaptations in the two genotypes. Shown on the x-axis is the number of trials after a successful reversal of behavior, i.e., trial n + 1 is the trial immediately following the final reversal error. The values on the y-axis are the percentage of the 18 reversals, in which the subjects maintain this newly correct response on trials n + 1 to n + 8. *p < 0.05.

Figure 3.

Signal change in response to negative feedback (ALLNEG − ALLPOS) superimposed on the MNI template brain. In both groups (A1−, top row; A1+, bottom row), there was increased activity in the RCZ (left), the ventral anterior insula (middle), and the middle frontal gyrus (right). Images are thresholded at z = 3.09. The color bar indicates z-scores. See supplemental Table S1, available at www.jneurosci.org as supplemental material, for a comprehensive list of all activations.

Figure 4.

Signal change in response to final reversal errors (FINREVERR − REVERR) superimposed on the MNI template brain. In the A1− group (top), there was significant signal change in the ventral anterior insula, lateral orbitofrontal cortex (left), the RCZ, and in dorsal and ventral aspects of the striatum (right). In addition, a region consistent with the location of the mesencephalic dopamine cell groups was found to be active (left). A similar pattern was found in the A1+ group (bottom); however, note the absence of the midbrain focus and the clearly diminished extent of lateral orbitofrontal activity (left). Furthermore, no significant signal change was found in the striatum, with the exception of a small focus of less than five voxels in the dorsolateral putamen (right). Images are thresholded at z = 3.09. The color bar indicates z-scores. See supplemental Table S2, available at www.jneurosci.org as supplemental material, for a comprehensive list of all activations.

Figure 5.

A direct comparison between the two genetic groups of the hemodynamic response to final reversal errors (A) (FINREVERR − REVERR) shows, at p < 0.01, an enhanced response in the right ventral striatum for the A1− group. The color bar indicates z-scores. B, Time course of hemodynamic activity in response to final reversal errors extracted from a 3 mm sphere centered around the peak coordinate of the contrast shown in A at MNI coordinates x = 17, y = 5, z = − 7. *p < 0.05.

Figure 6.

Time course of hemodynamic activity in response to final reversal errors extracted from a 3 mm sphere centered around the peak coordinate of the group difference in the right lateral orbitofrontal cortex (MNI coordinates: x = 53, y = 37, z = −5) between the A1− and the A1+ group. *p < 0.05.

Figure 7.

A, Contrast between negative feedback preceded by negative feedback in both of the two previous trials and negative feedback not preceded by any negative feedback (NEG + 2 − NEG + 0), compared between the two groups. At p < 0.005, there was an enhanced response in the RCZ for the A1− group. The color bar indicates z-scores. B, Time course of hemodynamic activity in NEG + 0, NEG + 1, and NEG + 2 trials. Time courses were extracted from a 3 mm sphere centered on the peak coordinate of the contrast shown in A at MNI x = 4, y = 30, z = 37. Time courses for the A1− group are shown in blue, for the A1+ group in red. *p < 0.05; NEG + 2 in A1− versus NEG + 2 in A1+. C, Amplitudes of the HRF calculated as the difference from baseline (mean from −4 s to event onset) to peak (mean from the time points 4 to 6 seconds after event onset), ^#p < 0.001.