1. Neuroscience
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PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

  1. Rachel A Ross  Is a corresponding author
  2. Silvia Leon
  3. Joseph C Madara
  4. Danielle Schafer
  5. Chrysanthi Fergani
  6. Caroline A Maguire
  7. Anne MJ Verstegen
  8. Emily Brengle
  9. Dong Kong
  10. Allan E Herbison
  11. Ursula B Kaiser
  12. Bradford B Lowell
  13. Victor M Navarro  Is a corresponding author
  1. Beth Israel Deaconess Medical Center, United States
  2. Harvard Medical School, United States
  3. University of Otago, New Zealand
  4. Brigham and Women's Hospital, United States
  5. Tufts University School of Medicine, United States
Research Article
  • Cited 33
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Cite this article as: eLife 2018;7:e35960 doi: 10.7554/eLife.35960

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with Adcyap1fl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction in female mice.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Rachel A Ross

    Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, United States
    For correspondence
    rross4@partners.org
    Competing interests
    The authors declare that no competing interests exist.

  2. Silvia Leon

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Joseph C Madara

    Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Danielle Schafer

    Centre for Neuroendocrinology, Department of Physiology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.

  5. Chrysanthi Fergani

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Caroline A Maguire

    Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Anne MJ Verstegen

    Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Emily Brengle

    Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Dong Kong

    Department of Neuroscience, Tufts University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Allan E Herbison

    Centre for Neuroendocrinology, Department of Physiology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9615-3022

  11. Ursula B Kaiser

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Bradford B Lowell

    Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Victor M Navarro

    Harvard Medical School, Boston, United States
    For correspondence
    vnavarro@bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5799-219X

Funding

National Institutes of Health (R01 HD090151-A1)

  • Victor M Navarro

National Institutes of Health (P30 DK057521)

  • Bradford B Lowell

National Institutes of Health (R01 HD082314)

  • Ursula B Kaiser

National Institutes of Health (R01 HD019938)

  • Ursula B Kaiser

National Institutes of Health (R00 HD071970)

  • Victor M Navarro

National Institutes of Health (5T32HL007374-36)

  • Rachel A Ross

National Institutes of Health (R01 DK075632)

  • Bradford B Lowell

National Institutes of Health (R01 DK089044)

  • Bradford B Lowell

National Institutes of Health (R01 DK111401)

  • Bradford B Lowell

National Institutes of Health (P30 DK046200)

  • Bradford B Lowell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal care and experimental procedures were approved by the National Institute of Health, Beth Israel Deaconess Medical Center and Brigham and Women's Hospital Institutional Animal Care and Use Committee . protocol #05165.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: February 16, 2018
  2. Accepted: June 14, 2018
  3. Accepted Manuscript published: June 15, 2018 (version 1)
  4. Version of Record published: June 21, 2018 (version 2)

Copyright

© 2018, Ross et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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