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Unformatted text preview: Long story short: the serotonin transporter in emotion regulation and social cognition Turhan Canli 1,2 & Klaus-Peter Lesch 3 The gene encoding the serotonin transporter (5-HTT) contains a regulatory variation that has been associated with anxiety-related traits and susceptibility for depression. Here we highlight recent discoveries related to allelic variation of 5-HTT function with respect to emotion regulation and social behavior, drawing from an interdisciplinary perspective of behavioral genetics and cognitive neuroscience. Following a reductionistic path that leads from gene-behavior association studies to neuroimaging and epigenetic studies, we compare two models of 5-HTT-dependent modulation of brain activity and discuss the role of life stress experience in modifying 5-HTT function in the brain. Integration of these findings suggests that the impact of the 5-HTT gene on behavior is much broader than is commonly appreciated and may have a role in social cognition. Serotonergic neurotransmission affects a wide range of behaviors, from food intake and reproductive activity, to sensory processing and motor activity, to cognition and emotion. One key regulator is the serotonin transporter (5-HTT), which removes serotonin released into the synaptic cleft. The 5-HTT protein is encoded by a single gene, SLC6A4 . Transcriptional activity of the human SLC6A4 is modulated by several variations, including a repetitive sequence, the SLC6A4- linked polymorphic region ( 5-HTTLPR ), which is composed of a short and a long version, which result in differential 5-HTT expression and function ( Fig. 1 ). In this review, we begin with association studies linking SLC6A4 variation to personality traits that are risk factors for affective spectrum disorders. We then discuss neuroimaging studies of intermediate or endophenotypes aimed at identifying the underlying neurobiological mechanisms. We speculate that interactions between gene and environ- ment involving SLC6A4 may modulate the mirror neuron system and Von Economo neurons within neural circuits involved in social cognition. We conclude with a view toward a social neuroscience of 5-HTT function. Serotonin transporter and neuroticism The contribution of SLC6A4 to individual differences in personality traits was initially explored in a population and family-based genetic study 1 showing a significant association between the low-expressing 5-HTTLPR short variant and neuroticism. This trait is related to anxiety, stress reactivity and depression. Individuals with either one or two copies of the 5-HTTLPR short variant had significantly higher scores of neuroticism than those who were homozygous for the 5-HTTLPR long variant. This association was replicated in an independent family-based sample 2 . Combined data from the two studies 2 , which were corrected for ethnicity and age, gave a highly significant association between the short variant and anxiety-related traits both across individuals and within families, suggesting a genuine...
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- Spring '10