Genetic variation in brain‐derived neurotrophic factor and human fear conditioning

Abstract

Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS ± 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning – evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

Gradients of Fear Potentiated Startle During Generalization, Extinction, and Extinction Recall—and Their Relations With Worry

“…Results indicated that generalization of conditioned fear to perceptually similar stimuli was indeed evident during the generalization phase. In line with previous studies of human fear generalization (Hajcak et al, 2009;Lissek et al, 2008;Lissek et al, 2010), we found that startle magnitude was largest to the CS+ and then gradually decreased as stimuli became less perceptually similar to the CS+. More specifically, compared to the safest stimulus (CS±60), potentiation of startle occurred to the CS+ and generalized to the next most similar shape (CS±20).…”

“…Using the same generalization paradigm mentioned previously (Lissek et al, 2008), results indicated that PD patients exhibited startle potentiation to the CS+, and this generalized to the three closest CS-(Class 4, 3, and 2), which resulted in a fear response gradient that was less steep than that of healthy controls (Lissek et al, 2009). Controls also exhibited startle potentiation to the CS+, but it only generalized to the one closest CS-(Class 4), which resulted in a steep and curvilinear generalization gradient that is typical of non-clinical humans and non-human animals (Hajcak et al, 2009;Lissek et al, 2009). Hence, both startle data and self-reported risk ratings indicated an overgeneralization of conditioned fear in PD.…”

“…Specifically, participants first underwent a fear generalization task in which they were exposed to a CS+ in addition to a range of GS stimuli (the same as reported in Hajcak et al (2009)); fear responses were assessed using the eyeblink startle reflex. We hypothesized that fear gradients in generalization would mimic previous studies, such that startle response would peak at the CS+ and steadily decrease as stimuli appeared less perceptually similar to the CS+.…”

Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research

“…Hajcak and colleagues (Hajcak et al, 2009) investigated the influence of BDNF on conditioned fear generalization in humans. Fifty-seven participants were genotyped and classified as carriers of the Val/Val BDNF allele (n = 44; 25 female), carriers of the Val/Met allele (n = 4; 3 female) or carriers of the Met/Met allele (n = 3; 1 female).…”

Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder

“…The possible role of conditioned fear-generalization in pathological anxiety has gained increased research recognition during the last decade (Vervliet, Vansteenwegen, & Eelen, 2004;Vervliet, Vansteenwegen, Baeyens, Hermans, & Eelen, 2005;Lissek et al, 2008bLissek et al, , 2010Lissek et al, , 2013Hajcak et al, 2009). Indeed, recent etiological accounts of anxiety disorders suggest that conditioned fear-generalization could be a central pathogenic marker of some anxiety disorders (Lissek, 2012), although prospective studies supporting this assumption are lacking.…”