PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

Significance Higher circulating pituitary adenylate cyclase-activating polypeptide (PACAP) and a polymorphism in its receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, have recently been linked with posttraumatic stress disorder (PTSD) in women and not men. The current study examined the influence of ADCYAP1R1 genotype on brain function among traumatized women. In individuals with the risk genotype, the amygdala showed greater reactivity to threat stimuli and decreased functional connectivity with the hippocampus. ADCYAP1R1 genotype had larger effects than PTSD diagnosis, suggesting that amygdala reactivity is an intermediate phenotype for anxiety-related psychopathology. Amygdala reactivity has been identified as a possible predisposing risk factor for PTSD, and the current findings indicate a possible genetic mechanism. Findings also point to a neurobiological explanation for increased PTSD prevalence in women. We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD and are known to have high densities of PACAP receptors. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.

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