Velasco, Eric R.Florido Torres, Antonio LuisFlores de los Heros, África, 1985-Senabre, EricGómez-Gómez, ÀlexTorres, AntoniRoca, AntoniNorrholm, SethNewman, Emily L.Das, PayelRoss, Rachel A.Lori, A.Pozo Mendoza, Óscar J., 1975-Ressler, Kerry J.Garcia-Esteve, LluïsaJovanovic, TanjaAndero, Raül2023-02-072023-02-072022Velasco ER, Florido A, Flores Á, Senabre E, Gomez-Gomez A, Torres A, Roca A, Norrholm S, Newman EL, Das P, Ross RA, Lori A, Pozo OJ, Ressler KJ, Garcia-Esteve LL, Jovanovic T, Andero R. PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus. Nat Commun. 2022 Jul 28;13(1):4374. DOI: 10.1038/s41467-022-31442-w2041-1723http://hdl.handle.net/10230/55663Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-022-31442-wFear conditioningNeuroscienceinfo:eu-repo/semantics/openAccess