Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task

Abstract

Prior work has highlighted the role of genetic variation within the repetitive sequence in the transcriptional control region of the serotonin (5-HT) transporter gene (5-HTT, SLC6A4) in modulating amygdala and prefrontal activation to negative emotional stimuli. However, these studies have not explicitly tested the assumption that the control condition (neutral baseline) does not itself produce changes in activation as a function of 5-HTT genotype. Using a fixation baseline condition, we show that variation in 5-HTT genotype is associated with differential activation to negative, positive, and neutral stimuli in limbic, striatal, and cortical regions. We replicate earlier reports of increased amygdala activation to negative, relative to neutral, stimuli, but then show that these differences are driven by decreased activation to neutral stimuli, rather than increased activation to negative stimuli, in carriers of the 5-HTT short allele. Using high-resolution structural images and automated processes to test for brain volume and gray matter density, we further report significant differences, as a function of 5-HTT genotype, in frontal cortical regions, anterior cingulate, and cerebellum. These functional and structural differences suggest a much broader role for 5-HT transport efficiency in brain processes than previously thought. 5-HTT genotype affects neural systems controlling affective, cognitive, and motor processes.

Fig. 1.

Amygdala activation to negative, neutral, and fixation stimuli. (Upper) Results of three separate contrast analyses, projecting significant clusters onto a coronal plane through the amygdala. (Lower) Corresponding bar graphs with percentage of signal change (±SEM) across the entire region of interest (ROI). A common ROI was used across all three analyses to extract individual mean activation values and was formed by the conjunction of the functionally defined ROIs in the negative-neutral and neutral-fixation contrasts (there was no significant cluster in the negative-fixation contrast).

Fig. 2.

Areas of significant group differences, as a function of 5-HTT genotype, to neutral words, compared with a fixation baseline condition. Bar graphs represent percentage of signal change (±SEM) across the entire cluster in the left (L) or right (R) hemisphere. The row of three numbers refers to Montreal Neurological Institute (MNI) coordinates of maximally significant voxel; the single number below refers to the cluster size in voxels. Significant differences from baseline are indicated by ^*, P < 0.05 and ^**, P < 0.01. PreCG, precentral gyrus; PostCG, postcentral gyrus; IPL, inferior parietal lobule; STG, superior temporal gyrus; MTG, middle temporal gyrus; ITG, inferior temporal gyrus; FG, fusiform gyrus; PC, posterior cingulate.