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

Abstract

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.

Keywords: emotion; fMRI; intermediate phenotype; single nucleotide polymorphism.

Fig. 1.

Effect of ADCYAP1R1 genotype on regional activation. (A) Increased activation within the amygdala ROI for the risk (CC, n = 22) relative to nonrisk (GC, GG, n = 27) group (left amygdala: Z = 2.59, k = 52, x, y, z = −20, −4, −12; right amygdala: Z = 2.53, k = 30, x, y, z = 24, 0, −12). (B) Increased activation within the hippocampus ROI for risk relative to nonrisk group (left hippocampus: Z = 3.18, k = 103, x, y, z = −16, −36, −8; right hippocampus: Z = 2.57, k = 67, x, y, z = 8, −36, −4). Significant clusters (p_corr < 0.05) are overlaid on slices from a representative ICBM 152 template brain. Slices are displayed in neurological orientation. Red–yellow color scale indicates increased activation for the risk group relative to the nonrisk group. Bar charts show the mean of contrast values across all voxels in the anatomical ROIs, for the fearful > neutral contrast. Error bars represent ±1 SEM.

Fig. 2.

Effect of ADCYAP1R1 genotype on functional connectivity between the amygdala and hippocampus. For voxels within a mask of the bilateral hippocampus, clusters that showed significant covariance with the amygdala seeds are overlaid on slices from a representative ICBM-152 template brain. (A) The risk group showed decreased connectivity relative to the nonrisk group, between the left amygdala and a cluster in right anterior hippocampus (p_corr < 0.05, Z = 2.95, k = 17, x, y, z = 32, −8, −32), displayed on sagittal and axial slices. (B) The risk group showed decreased connectivity relative to the nonrisk group, between the right amygdala and a cluster in left posterior hippocampus (p_corr < 0.05), displayed on sagittal and axial slices. Slices are displayed in neurological orientation. Blue–green color scale shows regions of decreased connectivity for the risk group (n = 22) relative to the nonrisk group (n = 27), for the fearful > neutral contrast.