Abstract
A variable number of tandem repeats (short (S) vs long (L)) in the promoter region of the serotonin transporter gene (5-HTTLPR) and a functional variant of a single-nucleotide polymorphism (rs25531) in 5-HTTLPR have been recently associated with increased risk for major depressive disorder (MDD). In particular, relative to L/L or LA homozygotes (hereafter referred to as L′ participants), S carriers or Lg-allele carriers (S′ participants) have been found to have a higher probability of developing depression after stressful life events, although inconsistencies abound. Previous research indicates that patients with MDD are characterized by executive dysfunction and abnormal activation within the anterior cingulate cortex (ACC), particularly in situations requiring adaptive behavioral adjustments following errors and response conflict (action monitoring). The goal of this study was to test whether psychiatrically healthy S′ participants would show abnormalities similar to those of MDD subjects. To this end, 19 S′ and 14 L′ participants performed a modified Flanker task known to induce errors, response conflict, and activations in various ACC subdivisions during functional magnetic resonance imaging. As hypothesized, relative to L′ participants, S′ participants showed (1) impaired post-error and post-conflict behavioral adjustments; (2) larger error-related rostral ACC activation; and (3) lower conflict-related dorsal ACC activation. As similar behavioral and neural dysfunctions have been recently described in MDD patient samples, the current results raise the possibility that impaired action monitoring and associated ACC dysregulation may represent risk factors increased vulnerability to depression.
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Acknowledgements
This study was funded by a Sackler Scholar in Psychobiology Research Grant (RB), a National Institute of Health Training Grant 1 F31MH078346 (AJH), and NIMH Research Grants R01MH68376 and R21MH078979 (DAP). We thank Nancy Brooks, Alison Brown, Daniel G Dillon, Jesen Fagerness, Miles Nugent, Roy H Perlis, Sara Rubenstein, and Patrice Vamivakas for their contributions and assistance with various aspects of this research.
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The authors declare that over the past 3 years, Dr Pizzagalli has received research support from GlaxoSmithKline, Merck and ANT North America (Advanced Neurotechnology) for projects unrelated to the current study; consulting fees from ANT and AstraZeneca, and honoraria from AstraZeneca. Dr Holmes and Mr Bogdan declare no competing interests.
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Holmes, A., Bogdan, R. & Pizzagalli, D. Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression. Neuropsychopharmacol 35, 1186–1197 (2010). https://doi.org/10.1038/npp.2009.223
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