1. Neuroscience
Download icon

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
  • Views 1,898
  • Annotations
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.

Metrics

  • 1,898
    Page views
  • 353
    Downloads
  • 33
    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)

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

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

Further reading

    1. Neuroscience
    Zhengchao Xu et al.
    Tools and Resources Updated

    The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions. However, their whole-brain input-output circuits remain incompletely elucidated. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We found that these neurons received inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus had divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons projected to the lateral habenula through multiple pathways. Correlation and cluster analysis revealed that glutamatergic and GABAergic neurons in the same raphe nucleus received heterogeneous inputs and sent different collateral projections. This connectivity atlas further elucidates the anatomical architecture of the raphe nuclei, which could facilitate better understanding of their behavioral functions.

    1. Neuroscience
    Shankar Ramachandran et al.
    Research Article Updated

    Neuromodulators promote adaptive behaviors that are often complex and involve concerted activity changes across circuits that are often not physically connected. It is not well understood how neuromodulatory systems accomplish these tasks. Here, we show that the Caenorhabditis elegans NLP-12 neuropeptide system shapes responses to food availability by modulating the activity of head and body wall motor neurons through alternate G-protein coupled receptor (GPCR) targets, CKR-1 and CKR-2. We show ckr-2 deletion reduces body bend depth during movement under basal conditions. We demonstrate CKR-1 is a functional NLP-12 receptor and define its expression in the nervous system. In contrast to basal locomotion, biased CKR-1 GPCR stimulation of head motor neurons promotes turning during local searching. Deletion of ckr-1 reduces head neuron activity and diminishes turning while specific ckr-1 overexpression or head neuron activation promote turning. Thus, our studies suggest locomotor responses to changing food availability are regulated through conditional NLP-12 stimulation of head or body wall motor circuits.