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Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions

  • Author Footnotes
    1 Authors FK and MK contributed equally to this work.
    Floris Klumpers
    Correspondence
    Address correspondence to Floris Klumpers, Ph.D., Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Kapittelweg 29, PO Box 9101, Nijmegen NL-6500, Netherlands
    Footnotes
    1 Authors FK and MK contributed equally to this work.
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen

    Department of Experimental Psychology, Utrecht University, Utrecht
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  • Author Footnotes
    1 Authors FK and MK contributed equally to this work.
    Marijn C. Kroes
    Footnotes
    1 Authors FK and MK contributed equally to this work.
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen
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  • Ivo Heitland
    Affiliations
    Department of Experimental Psychology, Utrecht University, Utrecht
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  • Daphne Everaerd
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen

    Department of Psychiatry, Radboud University Medical Center, Nijmegen
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  • Sophie E.A. Akkermans
    Affiliations
    Department of Experimental Psychology, Utrecht University, Utrecht
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  • Ronald S. Oosting
    Affiliations
    Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht
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  • Guido van Wingen
    Affiliations
    Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam
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  • Barbara Franke
    Affiliations
    Department of Psychiatry, Radboud University Medical Center, Nijmegen

    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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  • J. Leon Kenemans
    Affiliations
    Department of Experimental Psychology, Utrecht University, Utrecht
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  • Author Footnotes
    2 Authors GF and JMPB contributed equally to this work.
    Guillén Fernández
    Footnotes
    2 Authors GF and JMPB contributed equally to this work.
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen
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  • Author Footnotes
    2 Authors GF and JMPB contributed equally to this work.
    Johanna M.P. Baas
    Footnotes
    2 Authors GF and JMPB contributed equally to this work.
    Affiliations
    Department of Experimental Psychology, Utrecht University, Utrecht
    Search for articles by this author
  • Author Footnotes
    1 Authors FK and MK contributed equally to this work.
    2 Authors GF and JMPB contributed equally to this work.

      Abstract

      Background

      Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states.

      Methods

      The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals’ anticipatory responses to potential threat.

      Results

      Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2).

      Conclusions

      The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.

      Keywords

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      Linked Article

      • Serotonin Transporter Linked Polymorphic Region: From Behavior to Neural Mechanisms
        Biological PsychiatryVol. 78Issue 8
        • Preview
          The clinical efficacy of selective serotonin reuptake inhibitors that exert their therapeutic action via the serotonin transporter protein (SERT), which is coded by a single gene (SLC6A4), has fueled research over the past 3 decades. The first report on a functional degenerate repeat polymorphic region within SLC6A4 (serotonin-transporter-linked polymorphic region [5-HTTLPR]), associated with anxiety-related personality traits (1), made this genetic variant subject to numerous studies in animals, healthy humans, and psychiatric patients.
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      • Erratum
        Biological PsychiatryVol. 81Issue 8
        • Preview
          Erratum to: “Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions” by Klumpers et al. (Biol Psychiatry 2015; 78:582-589).
        • Full-Text
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