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Cereb Cortex. 2014 Sep;24(9):2421-9. doi: 10.1093/cercor/bht099. Epub 2013 Apr 15.

5-HTTLPR polymorphism modulates neural mechanisms of negative self-reflection.

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Department of Psychology, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
Peking-Tsinghua Center for Life Sciences at School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.


Cognitive distortion in depression is characterized by enhanced negative thoughts about both environment and oneself. Carriers of a risk allele for depression, that is, the short (s) allele of the serotonin transporter promoter polymorphism (5-HTTLPR), exhibit amygdala hyperresponsiveness to negative environmental stimuli relative to homozygous long variant (l/l). However, the neural correlates of negative self-schema in s allele carriers remain unknown. Using functional MRI, we scanned individuals with s/s or l/l genotype of the 5-HTTLPR during reflection on their own personality traits or a friend's personality traits. We found that relative to l/l carriers, s/s carriers showed stronger distressed feelings and greater activity in the dorsal anterior cingulate (dACC)/dorsal medial prefrontal cortex (dmPFC) and the right anterior insula (AI) during negative self-reflection. The 5-HTTLPR effect on the distressed feelings was mediated by the AI/inferior frontal (IF) activity during negative self-reflection. The dACC/dmPFC activity explained 20% of the variation in harm-avoidance tendency in s/s but not l/l carriers. The genotype effects on distress and brain activity were not observed during reflection on a friend's negative traits. Our findings reveal that 5-HTTLPR polymorphism modulates distressed feelings and brain activities associated with negative self-schema and suggest a potential neurogenetic susceptibility mechanism for depression.


5-HTTLPR; FMRI; anterior cingulate; anterior insula; negative self-schema

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