Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats

• Published in: Neuropharmacology Vol. 133; pp. 145 - 154
• Main Authors: Kirry, Adam J., Herbst, Matthew R., Poirier, Sarah E., Maskeri, Michelle M., Rothwell, Amy C., Twining, Robert C., Gilmartin, Marieke R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2018
• Subjects: Fear conditioning; Memory formation; Neuropeptide; PTSD; Sex difference; Working memory; PTSD; Working memory; Sex difference; Neuropeptide; Memory formation; Fear conditioning
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.01.010

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues. •Prefrontal PAC1 receptor signaling contributes to the strength of cued, but not contextual, fear memory.•The effects of blocking prefrontal PAC1 receptor signaling are specific to females.•Females exhibit greater PAC1 receptor mRNA expression compared with males.•Prefrontal PAC1 receptor signaling is a potential neurobiological substrate of PTSD in women.