Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex

Abstract

Dysregulated fear conditioned responses have been associated with PTSD in adults, with increased fear-potentiated startle (FPS) serving as a potential intermediate phenotype for PTSD risk. This phenotype has also been associated with stress-related ADCYAP1R1 gene variants in adult women. However, FPS and genotype have not yet been examined during development. The aim of this study was to examine developmental changes in fear conditioning, and to see whether these changes were impacted by genotype and trauma. Differential fear conditioning using FPS was tested in n = 63 children ages 8-13 at two visits (V1, V2) 1 year apart. Startle response was measured using electromyograph recordings of the eyeblink muscle. The rs2267735 SNP of the ADCYAP1R1 gene was extracted from genome-wide (GWAS) analyses. Trauma exposure was assessed using the Violence Exposure Scale-Revised (VEX-R). We found significant Visit by Genotype interactions, with CC genotype increasing FPS from V1 to V2. At V2 there was a Genotype by Violence interaction, with higher FPS in the CC vs G allele groups among those with higher violence exposure (F = 17.46, p = 0.0002). Females with the CC genotype had higher FPS compared to G allele females (F = 12.09, p = 0.002); there were no effects of genotype in males. This study showed Gene × Environment × Development and Gene × Sex effects of ADCYAP1R1 in a high-risk pediatric population. Those with the CC genotype and high levels of violence exposure, as well as females with the CC genotype, showed the greatest conditioned fear responses in adolescence.

The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli

“…Although these molecular hypotheses are beyond the scope of this study, our findings support current evidence endorsing this system as a relevant actor in the susceptibility to develop maladaptive stress responses ( Lutfy and Shankar, 2019 ). Indeed, rs2267735 polymorphism has been found to modulate a wide variety of psychological processes involved in trauma-related disorders such as fear conditioning discrimination ( Ressler et al, 2011 ), contextual fear acquisition ( Pohlack et al, 2015 ), and dark-enhanced and fear-potentiated startle responses ( Jovanovic et al, 2020 ). Likewise, patients with PTSD consistently present diminished fear extinction learning and an over-expression of fear when facing conditioned stimuli ( Seligowski et al, 2019 ; Norrholm and Jovanovic, 2018 ).…”

“…This growing body of evidence correlating the ADCYAP1R1 polymorphism to dysfunctional response after exposure to stress and trauma in psychopathological samples raises questions on whether the effect of this specific risk genotype can be observed in healthy endophenotypes. Recent research in healthy females exposed to trauma suggests that CC alleles (i.e., the risk genotype) are associated with increased fear-potentiated startle responses ( Jovanovic et al, 2020 ) and that this heightened response to threat stimuli coincides with greater activation in the amygdala and the hippocampus ( Stevens et al, 2014 ). In addition, there is evidence suggesting that PAC1R polymorphisms appear to modulate hippocampus engagement during the acquisition of contextual fear conditioning in healthy participants with heightened risk to experience traumatic events ( Pohlack et al, 2015 ).…”

Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory

“…In humans, the PTSD-related PAC1R risk allele is associated with enhanced startle to threat-related cues, impaired fear and safety discrimination, and altered hippocampal and amygdala reactivity in fear conditioning ( Ressler et al, 2011 ; Jovanovic et al, 2013 ; Stevens et al, 2014 ). In children, females with the risk allele showed enhanced fear responding to threat-related cues 1 year after conditioning ( Jovanovic et al, 2020 ). While these clinical studies implicate associative learning processes in the PAC1R-PTSD link, it is difficult to distinguish the unique contributions of associative learning vs stress reactivity.…”

PACAP‐expressing neurons in the lateral habenula diminish negative emotional valence

“…39,40 A single nucleotide polymorphism of the cognate receptor for PACAP, ADCYAP1R1, is associated with increased likelihood of developing posttraumatic stress disorder in adult women and female children. 41,42 While stress and the neuropeptide PACAP have a well-studied relationship, the role of PACAP-expressing neurons in the LHb on stressrelated behaviors has not been investigated. Therefore, in this study, we examined PACAP-expressing neurons in LHb in greater detail using a combination of transgenic PACAPpromoter Cre mice injected with a viral vector carrying a floxed hM 3 Dq DREADD receptor, allowing precise chemogenetic activation of PACAP neurons in LHb.…”