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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.

SUBMITTER: Stevens JS

PROVIDER: S-EPMC3939867 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Stevens Jennifer Strafford JS Almli Lynn M LM Fani Negar N Gutman David A DA Bradley Bekh B Norrholm Seth D SD Reiser Emily E Ely Timothy D TD Dhanani Rahim R Glover Ebony M EM Jovanovic Tanja T Ressler Kerry J KJ

Proceedings of the National Academy of Sciences of the United States of America 20140210 8

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 ...[more]

PMID: 24516127

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Project description:The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in neuromodulation of learning and memory. PACAP can alter synaptic plasticity and has direct actions on neurons in the amygdala and hippocampus that could contribute to its acute and persistent effects on the consolidation and expression of conditioned fear. We recently demonstrated that intracerebroventricular (ICV) infusion of PACAP prior to fear conditioning (FC) results in initial amnestic-like effects followed by hyper-expression of conditioned freezing with repeated testing, and analyses of immediate-early gene c-Fos expression suggested that the central nucleus of the amygdala (CeA), but not the lateral/basolateral amygdala (LA/BLA) or hippocampus, are involved in these PACAP effects. Here, we extend that work by examining the expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) after PACAP administration and FC. Male Sprague-Dawley rats were implanted with cannula for ICV infusion of PACAP-38 (1.5?µg) or vehicle followed by FC and tests for conditioned freezing. One hour after FC, Arc protein expression was significantly elevated in the CeA and bed nucleus of the stria terminalis (BNST), interconnected structures that are key elements of the extended amygdala, in rats that received the combination of PACAP?+?FC. In contrast, Arc expression within the subdivisions of the hippocampus, or the LA/BLA, were unchanged. A subpopulation of Arc-positive cells in both the CeA and BNST also express PKCdelta, an intracellular marker that has been used to identify microcircuits that gate conditioned fear in the CeA. Consistent with our previous findings, on the following day conditioned freezing behavior was reduced in rats that had been given the combination of PACAP?+?FC-an amnestic-like effect-and Arc expression levels had returned to baseline. Given the established role of Arc in modifying synaptic plasticity and memory formation, our findings suggest that PACAP-induced overexpression of Arc following fear conditioning may disrupt neuroplastic changes within populations of CeA and BNST neurons normally responsible for encoding fear-related cues that, in this case, results in altered fear memory consolidation. Hence, PACAP systems may represent an axis on which stress and experience-driven neurotransmission converge to alter emotional memory, and mediate pathologies that are characteristic of psychiatric illnesses such as post-traumatic stress disorder.

Dataset Information

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

Publications

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

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