Abstract
The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.
Highlights
From an evolutionary perspective, the acquisition of fear responses enables organisms to respond appropriately to predictors of aversive events [1,2]
During the uninstructed acquisition phase, significant potentiation of the eyeblink startle reflex to the threat cue was observed as indexed by contrasting startles during light on/CXT+ with startles during light off/CXT+
Simple main effect analysis using Tukey’s HSD Post-Hoc tests revealed that C/G carriers of corticotropin-releasing hormone receptor 1 (CRHR1) who were 5HTTLPR s-carriers showed a heightened context fear conditioned responses (FPS) when compared to CRHR1 C/C carriers with the 5HTTLPR s-carriers genotype (p = .02), and as a statistical trend when compared to CRHR1 C/G carriers with the 5HTTLPR s/s genotype (p = .09)
Summary
The acquisition of fear responses enables organisms to respond appropriately to predictors of aversive events [1,2] In the laboratory, this process is often modeled by classical fear conditioning procedures in which an originally neutral conditioned stimulus (CS; e.g. a light) is repeatedly paired with an unconditioned aversive stimulus (UCS; e.g. an electrical shock). Absence of the CS may come to signal periods of safety If this contingency is not acquired, threat remains unpredictable. This can result in chronic states of maladaptive anxiety in the context in which the CS is presented [3,4]. It remains largely unknown which neurotransmitter systems are involved in human fear acquisition deficits
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