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The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over-expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes.

Original publication




Journal article


Genes Brain Behav

Publication Date





330 - 336


5-HTT, 5-HTTLPR, SERT, ambiguous, animal model, cognitive bias, fear, mice, over-expressing, serotonin transporter, Animals, Conditioning, Classical, Cues, Discrimination (Psychology), Fear, Female, Male, Mice, Mice, Inbred C57BL, Serotonin Plasma Membrane Transport Proteins