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PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Author

Listed:
  • E. R. Velasco

    (Universitat Autònoma de Barcelona)

  • A. Florido

    (Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Á Flores

    (Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • E. Senabre

    (University Pompeu Fabra)

  • A. Gomez-Gomez

    (IMIM (Hospital del Mar Medical Research Institute))

  • A. Torres

    (Hospital Clínic, IDIBAPS
    Programme for the Prevention and Treatment of Psychic Effects in Sexually Assaulted Women. Hospital Clínic de Barcelona)

  • 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
    American Cancer Society, Inc.)

  • O. J. Pozo

    (IMIM (Hospital del Mar Medical Research Institute))

  • K. J. Ressler

    (Harvard Medical School)

  • L. L. Garcia-Esteve

    (Hospital Clínic, IDIBAPS
    Programme for the Prevention and Treatment of Psychic Effects in Sexually Assaulted Women. Hospital Clínic de Barcelona)

  • T. Jovanovic

    (Wayne State University)

  • R. Andero

    (Universitat Autònoma de Barcelona
    Instituto de Salud Carlos III
    Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona
    ICREA)

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.

Suggested Citation

  • 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-Estev, 2022. "PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31442-w
    DOI: 10.1038/s41467-022-31442-w
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    References listed on IDEAS

    as
    1. Kerry J. Ressler & Kristina B. Mercer & Bekh Bradley & Tanja Jovanovic & Amy Mahan & Kimberly Kerley & Seth D. Norrholm & Varun Kilaru & Alicia K. Smith & Amanda J. Myers & Manuel Ramirez & Anzhelika , 2011. "Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor," Nature, Nature, vol. 470(7335), pages 492-497, February.
    2. Ed S. Lein & Michael J. Hawrylycz & Nancy Ao & Mikael Ayres & Amy Bensinger & Amy Bernard & Andrew F. Boe & Mark S. Boguski & Kevin S. Brockway & Emi J. Byrnes & Lin Chen & Li Chen & Tsuey-Ming Chen &, 2007. "Genome-wide atlas of gene expression in the adult mouse brain," Nature, Nature, vol. 445(7124), pages 168-176, January.
    3. A. Florido & E. R. Velasco & C. M. Soto-Faguás & A. Gomez-Gomez & L. Perez-Caballero & P. Molina & R. Nadal & O. J. Pozo & C. A. Saura & R. Andero, 2021. "Sex differences in fear memory consolidation via Tac2 signaling in mice," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Kerry J. Ressler & Kristina B. Mercer & Bekh Bradley & Tanja Jovanovic & Amy Mahan & Kimberly Kerley & Seth D. Norrholm & Varun Kilaru & Alicia K. Smith & Amanda J. Myers & Manuel Ramirez & Anzhelika , 2011. "Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor," Nature, Nature, vol. 477(7362), pages 120-120, September.
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