PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

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 (...

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Bibliographic Details
Authors: Velasco, ER, Florido, A, Flores, A, 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
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repository:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p1618
Online Access:https://i3pt.portalinvestigacion.com/publicaciones/1618
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85135194989&doi=10.1038%2fs41467-022-31442-w&partnerID=40&md5=ec2f1d8fbea08a5558597bedf5963ab7
Access Level:Open access
Keyword:Animals
Extinction, Psychological
Fear
Female
Humans
Hypothalamus
Mice
Pituitary Adenylate Cyclase-Activating Polypeptide
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
hypophysis adenylate cyclase activating polypeptide
hypophysis adenylate cyclase activating polypeptide receptor 1
brain
gene expression
genotype
polymorphism
protein
RNA
animal
fear
female
genetics
human
hypothalamus
metabolism
mouse
physiology
reinforcement (psychology)
Description
Summary: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/Delta FosB 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. The PACAP-PAC1R neuropeptide system regulates neuroendocrine stress responses. Here the authors demonstrate a role for PACAP-PAC1R in ventromedial hypothalamus in modulating fear extinction.

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