Human Fear Acquisition Deficits in Relation to Genetic Variants of the Corticotropin Releasing Hormone Receptor 1 and the Serotonin Transporter

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.

The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear

“…The data analyzed in this study come from a sample reported on previously (Heitland et al, , 2013. The sample included 150 subjects recruited via advertisements at Utrecht University comprising 90 females and 60 males (mean age = 21.6, SD = 2.4) free of any current or previous psychiatric or neurological disorder, drug or alcohol dependence, current psychoactive medication, hearing problems and color blindness.…”

“…The study comprised a fear-potentiated startle (FPS) conditioning paradigm in a virtual reality environment (see Heitland et al, 2012Heitland et al, , 2013. In this paradigm, fear conditioned responding to both a threat cue and a threat context is acquired.…”

“…Many individual difference factors have been investigated that determine adaptive acquisition, expression, and extinction of conditioned fear responses, among which cue awareness (Hamm and Vaitl, 1996;Grillon, 2002;Baas et al, 2008), personality (Baas, 2013;Glotzbach-Schoon et al, 2013a) and genetic factors (e.g. Glotzbach-Schoon et al, 2013b;Heitland et al, 2012Heitland et al, , 2013Klumpers et al, 2012;Muhlberger et al, 2014; see Lonsdorf and Kalisch, 2011 for an overview). In general, replication studies of such findings are scarce, and therefore an important aim of this paper is to replicate some of our previous findings (Baas et al, 2008;Baas, 2013) in a larger sample.…”

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…In the context of PD, linkage and case/control studies as well as dimensional association studies provided a heterogeneous picture [26][27][28][29] regarding an involvement of CRHR1. Notably, the initial association of this gene with PD 29 was followed up recently, providing evidence that the CRHR1 minor rs878886 allele leads to fearacquisition deficits using a fear condition protocol in healthy volunteers 30 . Furthermore, a neuroimaging study revealed that the processing of emotional stimuli crucially depends on CRHR1 genotype 31 .…”

What can HPA axis-linked genes tell us about anxiety disorders in adolescents?

“…50 Fear acquisition deficit is relevant in the pathogenesis of human AD. 51 Finally, we evaluated the rs746530 polymorphism of the SERPINA6 gene in AD.…”