Altered lateral prefrontal cortex function is one of the most consistently reported findings in major depressive disorder (MDD) 
. Both increased and decreased functioning in the medial- and lateral prefrontal cortex during working memory related tasks have been demonstrated in MDD relative to healthy control subjects 
, and these activation patterns appear to contribute to the development and progression of MDD. It is unclear, however, if these alterations represent a vulnerability factor that increases the risk for developing MDD, or rather develops as a consequence of MDD. The serotonin transporter polymorphism (5-HTTLPR), with a variable number of DNA sequence repeats (short and long alleles) located in the regulatory region of the gene, has repeatedly been shown to moderate MDD risk 
. Several studies have demonstrated that short 5-HTTLPR carriers, particularly women 
, have increased vulnerability for the development of MDD in the context of stressful life events 
. Cognitive control is a key process in an integrated cognitive-biological model of depression 
, but 5-HTTLPR influence on this top-down part of the system has not been systematically investigated. This is in contrast to a number of studies on the limbic system based bottom-up pathway. In particular, the amygdala's role in the perception of emotional valence has led to a series of studies to determine the role of the 5-HTTLPR in processing emotionally salient information in MDD 
. Short 5-HTTLPR carriers have shown highly significant reduction of amygdala-anterior cingulate cortex connectivity in comparison to homozygote long 5-HTTLPR carriers 
. Short 5-HTTLPR carriers have also shown more functional coupling between the amygdala and the ventromedial prefrontal cortex, compared to long 5-HTTLPR carriers 
. There is also evidence of 5-HTTLPR-dependent structural variability in the MDD circuit that provides cognitive control of emotion (11). However, functional imaging studies on cognitive control are sparse. Cognitive control of emotion plays an important role in emotion downregulation when emotion activation is no longer adaptive 
. Therefore, individual differences in the ability to perform emotion downregulation may contribute in an important way to the risk for developing MDD.
Herein, we determine intermediate endophenotypes in a circuit that has been consistently implicated in MDD 
in healthy women at increased risk for developing MDD 
. We used fMRI and an n-back task to unmask altered brain function in healthy women who were grouped by 5-HTTLPR genotypes. We tested the hypothesis that short 5-HTTLPR allele carriers, but not long 5-HTTLPR carriers may be normal under resting conditions but show altered brain function while performing the n-back task as expressed by elevated activation within the lateral prefrontal cortex. Subregions within the ventrolateral prefrontal cortex were predefined based on its role in conscious emotion regulation 
. The activation pattern would be similar to what has been shown in individuals during a MDD episode 
. We also predicted that short 5-HTTLPR carriers would have weaker performance on the n-back task and that performancewill be inversely associated with lateral PFC activation.