A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults

Abstract

Poor fear extinction learning and recall are linked to the development of fear‐based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear‐related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat‐related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma‐related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive‐reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear‐related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N = 59; C/C = 35, A‐carrier = 24). We found lesser amygdala activation in A‐allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A‐carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.

FAAH polymorphism (rs324420) modulates extinction recall in healthy humans: an fMRI study

“…Furthermore, a dysfunction in networks including ACC and AIC has been discussed as a potential transdiagnostic marker in psychiatric disorders [ 25 – 27 ]. Using a region of interest approach, Zabik et al [ 19 ] found less amygdala activation related to the previously extinguished cue in A-allele carriers, which could be interpreted in line with our findings. However, as Zabik et al [ 19 ] investigated trauma-exposed individuals and memory consolidation was only allowed for only 10 min after conditioning in 45 of 59 subjects, comparability of the studies remains unclear.…”

“…However, as Zabik et al [19] investigated trauma-exposed individuals and memory consolidation was only allowed for only 10 min after conditioning in 45 of 59 subjects, comparability of the studies remains unclear. Furthermore, while fear ratings in our study confirmed the validity of our conditioning-extinction-extinction recall paradigm [22], neither skin conductance measures nor subjective fear ratings were presented to demonstrate that the unconditioned stimulus (3D virtual snake striking toward participant's viewpoint) used was indeed suited to induce fear [19]. Following previous studies, the ACC seems to play a major role during fear extinction recall in PTSD patients, who frequently show disturbances in extinction recall and exhibit altered activation of the ACC, the hippocampus, amygdala, and ventromedial prefrontal cortex, as compared to trauma-exposed healthy controls [30][31][32].…”

“…In another fMRI study with healthy humans [ 18 ], A-allele carriers displayed enhanced frontal cortex–amygdala connectivity during rest, but no differences in emotion regulation strategies during a paradigm with negative pictures [ 18 ]. Furthermore, Zabik et al [ 19 ] showed genotype-dependent differential activation in brain regions related to fear conditioning and extinction using an associative learning task, however without effects on the behavioral level [ 19 ]. Combined, the A-allele of the SNP rs324420 has been linked to modulate pain perception [ 20 ], lower anxiety [ 7 ], and enhanced fear extinction learning [ 8 ].…”

The influence of FAAH genetic variation on physiological, cognitive, and neural signatures of fear acquisition and extinction learning in women with PTSD

“…Consistent with a recent investigation among healthy adults ( Zabik et al, 2021 ), our physiological indices of fear learning suggest that both groups (CC vs AA/AC allele carriers) exhibited differential responding to the CS+ vs CS- during acquisition and decreased (and non-differential) responding to CS during extinction, suggesting successful acquisition and extinction learning occurred. However, as was the case with the neuroimaging outcomes, the physiological and cognitive signatures of fear acquisition and extinction learning varied as a function of genetic variation within the FAAH C385 gene.…”

“…To date, the majority of research focused on the impact of elevated AEA levels (often due to FAAH genetic variation or administration of FAAH inhibitor) on fear conditioning processes has primarily reported on accelerated extinction learning and enhanced recall, with the majority of investigations (all but Ney et al, 2021b ) being conducted in healthy individuals without a clinical diagnosis such as PTSD ( Dincheva et al, 2015 , Mayo et al, 2020a , Mayo et al, 2020b , Zabik et al, 2021 ). Given that this is the first functional neuroimaging study to examine a clinical population (PTSD), and due to differences in task design, our ability to directly compare and contrast our findings with the existing literature is limited.…”