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

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.

Metrics

  • 2,060
    Page views
  • 374
    Downloads
  • 40
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rachel A Ross
  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
(2018)
PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse
eLife 7:e35960.
https://doi.org/10.7554/eLife.35960

Further reading

    1. Neuroscience
    Payel Chatterjee et al.
    Research Article

    During flight maneuvers, insects exhibit compensatory head movements which are essential for stabilizing the visual field on their retina, reducing motion blur, and supporting visual self-motion estimation. In Diptera, such head movements are mediated via visual feedback from their compound eyes that detect retinal slip, as well as rapid mechanosensory feedback from their halteres - the modified hindwings that sense the angular rates of body rotations. Because non-Dipteran insects lack halteres, it is not known if mechanosensory feedback about body rotations plays any role in their head stabilization response. Diverse non-Dipteran insects are known to rely on visual and antennal mechanosensory feedback for flight control. In hawkmoths, for instance, reduction of antennal mechanosensory feedback severely compromises their ability to control flight. Similarly, when the head movements of freely-flying moths are restricted, their flight ability is also severely impaired. The role of compensatory head movements as well as multimodal feedback in insect flight raises an interesting question: in insects that lack halteres, what sensory cues are required for head stabilization? Here, we show that in the nocturnal hawkmoth Daphnis nerii, compensatory head movements are mediated by combined visual and antennal mechanosensory feedback. We subjected tethered moths to open-loop body roll rotations under different lighting conditions, and measured their ability to maintain head angle in the presence or absence of antennal mechanosensory feedback. Our study suggests that head stabilization in moths is mediated primarily by visual feedback during roll movements at lower frequencies, whereas antennal mechanosensory feedback is required when roll occurs at higher frequency. These findings are consistent with the hypothesis that control of head angle results from a multimodal feedback loop that integrates both visual and antennal mechanosensory feedback, albeit at different latencies. At adequate light levels, visual feedback is sufficient for head stabilization primarily at low frequencies of body roll. However, under dark conditions, antennal mechanosensory feedback is essential for the control of head movements at high of body roll.

    1. Developmental Biology
    2. Neuroscience
    Ashtyn T Wiltbank et al.
    Research Article

    Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.