PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

E. R. Velasco; A. Florido; empty 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:https://doi.org/10.1038/s41467-022-31442-w

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

E. R. Velasco, A. Florido, empty 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^*

^*Corresponding author for this work

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

1 Citation (Scopus)

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
Article number	4374
Pages (from-to)	1-17
Number of pages	18
Journal	Nature communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-31442-w
Publication status	Published - Jul 2022

Keywords

Animals
Extinction, Psychological
Fear/physiology
Female
Humans
Hypothalamus/metabolism
Mice
Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/genetics

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https://doi.org/10.1038/s41467-022-31442-wLicence: CC BY

https://ddd.uab.cat/record/264807

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Velasco, E. R., Florido, A., Flores, E., 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, 1-17. [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.",

keywords = "Animals, Extinction, Psychological, Fear/physiology, Female, Humans, Hypothalamus/metabolism, Mice, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/genetics",

author = "Velasco, {E. R.} and A. Florido and empty 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",

note = "{\textcopyright} 2022. The Author(s).",

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doi = "https://doi.org/10.1038/s41467-022-31442-w",

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Velasco, ER, Florido, A, Flores, E, 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 2022, 'PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus', Nature communications, vol. 13, 4374, pp. 1-17. https://doi.org/10.1038/s41467-022-31442-w

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.

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

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DO - https://doi.org/10.1038/s41467-022-31442-w

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VL - 13

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M1 - 4374

ER -

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

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GMBCrossTalk-Food: Involvement of the gut microbiota-brain cross talk in the loss of eating control

Tratamiento preventivo e identificación de biomarcadores de diagnóstico precoz para el trastorno de estrés postraumático en adolescentes.

BioStress: Translational biomarkers of traumatic stress

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PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Abstract

Keywords

Access to Document

Other files and links

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GMBCrossTalk-Food: Involvement of the gut microbiota-brain cross talk in the loss of eating control

Tratamiento preventivo e identificación de biomarcadores de diagnóstico precoz para el trastorno de estrés postraumático en adolescentes.

BioStress: Translational biomarkers of traumatic stress

Cite this