title: Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions.
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.
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen; Department of Experimental Psychology, Utrecht University, Utrecht. Electronic address: F.Klumpers@fcdonders.ru.nl.
authors.forename: Floris
authors.initials: F
authors.lastname: Klumpers
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen.
authors.forename: Marijn C
authors.initials: MC
authors.lastname: Kroes
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht.
authors.forename: Ivo
authors.initials: I
authors.lastname: Heitland
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen; Department of Psychiatry, Radboud University Medical Center, Nijmegen.
authors.forename: Daphne
authors.initials: D
authors.lastname: Everaerd
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht.
authors.forename: Sophie E A
authors.initials: SE
authors.lastname: Akkermans
authors.affiliation: Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Oosting
authors.affiliation: Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam.
authors.forename: Guido
authors.initials: G
authors.lastname: van Wingen
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht.
authors.forename: J Leon
authors.initials: JL
authors.lastname: Kenemans
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen.
authors.forename: Guillén
authors.initials: G
authors.lastname: Fernández
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht.
authors.forename: Johanna M P
authors.initials: JM
authors.lastname: Baas
mesh_terms: D000328:Adult; D000483:Alleles; D001007:Anxiety / Q000235:genetics*; D001931:Brain Mapping / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011603:Psychophysiology; D013216:Reflex, Startle / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: 5-HTTLPR; Anxiety; Fear; Psychophysiology; Serotonin transporter; fMRI