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Biol Psychiatry. 2015 Oct 15;78(8):582-9. doi: 10.1016/j.biopsych.2014.07.034. Epub 2014 Aug 27.

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

Author information

1
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.
2
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen.
3
Department of Experimental Psychology, Utrecht University, Utrecht.
4
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen; Department of Psychiatry, Radboud University Medical Center, Nijmegen.
5
Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht.
6
Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam.
7
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.

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:

5-HTTLPR; Anxiety; Fear; Psychophysiology; Serotonin transporter; fMRI

PMID:
25444169
DOI:
10.1016/j.biopsych.2014.07.034
[Indexed for MEDLINE]

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