PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

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• dc.contributor.author Velasco, Eric R.
• dc.contributor.author Florido Torres, Antonio Luis
• dc.contributor.author Flores de los Heros, África, 1985-
• dc.contributor.author Senabre, Eric
• dc.contributor.author Gómez-Gómez, Àlex
• dc.contributor.author Torres, Antoni
• dc.contributor.author Roca, Antoni
• dc.contributor.author Norrholm, Seth
• dc.contributor.author Newman, Emily L.
• dc.contributor.author Das, Payel
• dc.contributor.author Ross, Rachel A.
• dc.contributor.author Lori, A.
• dc.contributor.author Pozo Mendoza, Óscar J., 1975-
• dc.contributor.author Ressler, Kerry J.
• dc.contributor.author Garcia-Esteve, Lluïsa
• dc.contributor.author Jovanovic, Tanja
• dc.contributor.author Andero, Raül
• dc.date.accessioned 2023-02-07T13:07:33Z
• dc.date.available 2023-02-07T13:07:33Z
• dc.date.issued 2022
• dc.description.abstract Exposure 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.
• dc.description.sponsorship We thank Drs. Javier Carrasco, Núria Barba, Mar Castillo, Roser Nadal, Antonio Armario, Laura Perez-Caballero and Ignacio Marín Blasco at the Institute of Neurosciences, UAB. RA was supported by a NARSAD Young Investigator Grant #22434, Ramón y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R FEDER funds and PID2020-112705RB-I00 FEDER funds, ERANET-Neuron JTC 2019 ISCIII AC19/00077 and Fundación Koplowitz. A.F. received the predoctoral fellowship 2018 FI_B00030 from Generalitat de Catalunya. E.R.V. was supported by the BES-2017-080870 FPI-2017 fellowship from MINECO. Á.F. was supported by FJCI-2016-29888 contract from MICINN. L.L.G.E. was a recipient of a grant from the Women’s Institute of Spain (235/09). O.P. was supported by the Spanish Health National System CPII16/00027. K.J.R. and E.L.N. were supported by NIH P50 MH115874. E.L.N. was supported by NIH F32MH125634. R.A.R. and P.D. are supported by NIH K08 DK118201. S.N. received funding from VA Merit and Department of Defense.
• dc.format.mimetype application/pdf
• dc.identifier.citation Velasco 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-w
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-31442-w
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/55663
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2022 Jul 28;13(1):4374
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RYC2014-15784
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-76565-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-112705RB-I00
• dc.rights © 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/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Fear conditioning
• dc.subject.keyword Neuroscience
• dc.title PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion