TY - JOUR
T1 - PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus
AU - Velasco, E. R.
AU - Florido, A.
AU - Flores, empty
AU - Senabre, E.
AU - Gomez-Gomez, A.
AU - Torres, A.
AU - Roca, A.
AU - Norrholm, S.
AU - Newman, E. L.
AU - Das, P.
AU - Ross, R. A.
AU - Lori, A.
AU - Pozo, O. J.
AU - Ressler, K. J.
AU - Garcia-Esteve, L. L.
AU - Jovanovic, T.
AU - Andero, R.
N1 - © 2022. The Author(s).
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Animals
KW - Extinction, Psychological
KW - Fear/physiology
KW - Female
KW - Humans
KW - Hypothalamus/metabolism
KW - Mice
KW - Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism
KW - Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/genetics
UR - https://www.scopus.com/pages/publications/85135194989
UR - https://www.mendeley.com/catalogue/00439cde-0e95-36cc-ae21-dff2870b8bd6/
UR - https://portalrecerca.uab.cat/en/publications/d208b24f-fcf8-4f6f-8a7c-c126e1b32206
U2 - 10.1038/s41467-022-31442-w
DO - 10.1038/s41467-022-31442-w
M3 - Article
C2 - 35902577
AN - SCOPUS:85135194989
SN - 2041-1723
VL - 13
SP - 1
EP - 17
JO - Nature communications
JF - Nature communications
M1 - 4374
ER -