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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Article info
Publication history
Published online: August 26, 2014
Accepted:
July 25,
2014
Received in revised form:
July 18,
2014
Received:
March 8,
2014
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Serotonin Transporter Linked Polymorphic Region: From Behavior to Neural MechanismsBiological PsychiatryVol. 78Issue 8
- PreviewThe 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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- ErratumBiological PsychiatryVol. 81Issue 8
