PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

E. R. Velasco, A. Florido, Á Flores, E. Senabre, A. Gomez-Gomez, A. Torres, A. Roca, S. Norrholm, E. L. Newman, P. Das, R. A. Ross, A. Lori, O. J. Pozo, K. J. Ressler, L. L. Garcia-Esteve, T. Jovanovic and R. Andero ()
Additional contact information
E. R. Velasco: Universitat Autònoma de Barcelona
A. Florido: Universitat Autònoma de Barcelona
Á Flores: Universitat Autònoma de Barcelona
E. Senabre: University Pompeu Fabra
A. Gomez-Gomez: IMIM (Hospital del Mar Medical Research Institute)
A. Torres: Hospital Clínic, IDIBAPS
A. Roca: Hospital Clínic, IDIBAPS
S. Norrholm: Wayne State University
E. L. Newman: Harvard Medical School
P. Das: Psychiatry Research Institute of Montefiore and Einstein
R. A. Ross: Psychiatry Research Institute of Montefiore and Einstein
A. Lori: Emory University
O. J. Pozo: IMIM (Hospital del Mar Medical Research Institute)
K. J. Ressler: Harvard Medical School
L. L. Garcia-Esteve: Hospital Clínic, IDIBAPS
T. Jovanovic: Wayne State University
R. Andero: Universitat Autònoma de Barcelona

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31442-w

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