AbstractBackground: The serotonin transporter (5-HTTLPR) short allele has reduced transcriptional efficiency compared to the long allele, and individuals carrying the short allele tend to have increased risk for depression. Major Depressive Disorder is characterized by region-specific anterior cingulate cortex (ACC) dysfunction. However, whether this represents a trait marker of depressive mood or a vulnerability factor has not yet been addressed. A logical approach to answer this question is to study healthy individuals with or without genetic risk. The main aim of this study was to explore whether ACC activation is associated with 5-HTTLPR variants when cognitive load increases in healthy subjects. A secondary aim was to investigate behavioural data from the fMRI events and its potential association with functional activity within the anterior cingulate.Methods: A total of 38 healthy female participants, screened for symptomatology related to anxiety and depression, were included in the fMRI study. Participants were genotyped according to the 5-HTTLPR triallelic model. Cognitive load was measured in an fMRI modified n-back procedure.Results: The main finding was that dorsal ACC activation increased with the number of short alleles and cognitive load. The behavioural data showed significant group differences on 3-back accuracy, such that the short allele carriers made the most errors. Conclusion: The increased dorsal ACC activation is interpreted as a cognitive compensation mechanism, whereby it is suggested that SS carriers find the task the most difficult. This may indicate an association between 5-HTTLPR variability and cognitive vulnerability.