In order to enable goal-directed behavior in a dynamically changing environment, the human brain must meet two competing requirements: (1) the goal representations must be stably and robustly maintained in the face of interference, and (2) the same goal representations must be rapidly and flexibly adjusted in response to changes in the environment. The amygdala–prefrontal cortex (PFC) circuitry is thought to be critically involved in balancing these two processing demands. It is therefore critical to elucidate the factors that modulate amygdala–PFC circuit function and that contribute to its dysregulation in psychopathology.

Growing evidence suggests that genetic factors impact the amygdala–PFC circuitry. In particular, several studies have shown that variation in the serotonin transporter (5-HTT) gene alters the response and functional connectivity within the amygdala–PFC circuit during emotion processing. In contrast, the effects of 5-HTT gene variation on the amygdala–PFC circuit function in cognition and goal-directed behavior are not well understood.

The purpose of this dissertation was to investigate the impact of two functional polymorphisms in the 5-HTT gene (the 5-HTT-linked polymorphic region [5-HTTLPR], including the rs25531 SNP, and the serotonin transporter intron 2 [STin2]) on the neural and behavioral correlates of goal-directed cognition, using behavioral genetics and imaging genetics approaches. The results of Study 1 suggest that 5-HTT gene variation modulates susceptibility to response interference from both neutral and emotionally salient distracters during task performance (Requirement 1). In Study 2, employing an imaging genetics approach and a computer-tailored smoking-cessation intervention, we show that 5-HTT gene variation modulates the response and functional connectivity in the amygdala–PFC circuit when processing smoking-cessation messages in a manner that affects subsequent goal attainment, i.e., successful smoking cessation (Requirement 2).

Taken together, these studies demonstrate the impact of 5-HTT gene variation on two aspects of goal-directed cognition subserved by the amygdala–PFC circuit: resisting response interference from goal-irrelevant distracters, and updating a goal representation in response to goal-relevant stimuli. These findings add to our mechanistic understanding of the amygdala–PFC circuit involvement in goal-directed behavior and may shed light on the nature of dysregulation of this circuitry in psychopathology.