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.amygdala ͉ polymorphism ͉ 5-HTT

Gene–gene effects on central processing of aversive stimuli

“…66 The effect of 5-HTTLPR on extra-limbic cortical activation by affective stimuli was recently reported. 67 Therefore, we explored whether the assessed genotypes also affect processing of affective stimuli outside the limbic system and observed that processing of aversive stimuli was affected in the PFC, insula, and temporal, parietal and occipital cortices (data not shown). Further studies should investigate COMT and 5-HTT genotype effects on cognitive function and extra-limbic brain areas.…”

Stop the sadness: Neuroticism is associated with sustained medial prefrontal cortex response to emotional facial expressions

“…The time-course and order of block presentations in the current task also limited our analysis by only being able to use neutral as a baseline condition. We have previously reported on individual differences in resting (fixation) brain activity (Canli et al, 2005(Canli et al, , 2006). In the current series of analysis, we were interested in identifying temporal changes in activity and therefore chose neutral as a baseline based on the comparable timecourse of this condition compared to each of the emotional conditions (4 18-second blocks).…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…99 Studies that include a passive baseline (fixation cross) show that the apparent over-reactivity to negative stimuli is largely explained by decreased reactivity of the amygdala to neutral stimuli compared to the passive baseline. 100,101 This pattern of findings may reflect an increased resting amygdala activity in s allele carriers, but this would have to be tested using a method with an absolute baseline. Using MRI perfusion imaging, Canli and colleagues found support for increased resting activity in the left amygdala and the hippocampus.…”

“…103 Furthermore, a whole brain exploration indicates widespread structural and functional differences between s allele carriers and ll homozygotes in other brain regions: the s allele appears to be associated with reduced volume and grey matter density in several frontal-lobe regions, greater reactivity to negative emotional stimuli in the insula and striatum and stronger reactivity to positive emotional stimuli in the left frontal and posterior cingulate regions. 100 These results, contingent on replication, indicate that the 5-HTTLPR may have a pervasive effect on brain structure and function.…”