PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

E. R. Velasco; A. Florido; 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; R. Andero

doi:10.1038/s41467-022-31442-w

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

E. R. Velasco, A. Florido, 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, R. Andero

Neuroscience

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Article number	4374
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31442-w
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Velasco, E. R., Florido, A., Flores, Senabre, E., Gomez-Gomez, A., Torres, A., Roca, A., Norrholm, S., Newman, E. L., Das, P., Ross, R. A., Lori, A., Pozo, O. J., Ressler, K. J., Garcia-Esteve, L. L., Jovanovic, T., & Andero, R. (2022). PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus. Nature communications, 13(1), Article 4374. https://doi.org/10.1038/s41467-022-31442-w

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title = "PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus",

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.",

author = "Velasco, {E. R.} and A. Florido and Flores and E. Senabre and A. Gomez-Gomez and A. Torres and A. Roca and S. Norrholm and Newman, {E. L.} and P. Das and Ross, {R. A.} and A. Lori and Pozo, {O. J.} and Ressler, {K. J.} and Garcia-Esteve, {L. L.} and T. Jovanovic and R. Andero",

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doi = "10.1038/s41467-022-31442-w",

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AU - Velasco, E. R.

AU - Florido, A.

AU - Flores,

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.

PY - 2022/12

Y1 - 2022/12

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.

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PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Abstract

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