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Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network

  1. Margaritis Voliotis  Is a corresponding author
  2. Xiao Feng Li
  3. Ross Alexander De Burgh
  4. Geffen Lass
  5. Deyana Ivanova
  6. Caitlin McIntyre
  7. Kevin O’Byrne
  8. Krasimira Tsaneva-Atanasova
  1. University of Exeter, United Kingdom
  2. King's College London, United Kingdom
  3. Exeter University, United Kingdom
Research Article
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Cite this article as: eLife 2021;10:e71252 doi: 10.7554/eLife.71252

Abstract

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

Data availability

The data and the code are publicly available via the following open access repositories:http://doi.org/doi:10.18742/RDM01-750https://git.exeter.ac.uk/mv286/kndy-parameter-inference.git

The following data sets were generated

Article and author information

Author details

  1. Margaritis Voliotis

    Mathematics, University of Exeter, Exeter, United Kingdom
    For correspondence
    m.voliotis@exeter.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6488-7198
  2. Xiao Feng Li

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Ross Alexander De Burgh

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Geffen Lass

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Deyana Ivanova

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Caitlin McIntyre

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Kevin O’Byrne

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Krasimira Tsaneva-Atanasova

    Department of Mathematics and Living Systems Institute, Exeter University, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6294-7051

Funding

Engineering and Physical Sciences Research Council (EP/N014391/1)

  • Margaritis Voliotis
  • Krasimira Tsaneva-Atanasova

Biotechnology and Biological Sciences Research Council (BB/S000550/1)

  • Margaritis Voliotis
  • Xiao Feng Li
  • Kevin O’Byrne
  • Krasimira Tsaneva-Atanasova

Biotechnology and Biological Sciences Research Council (BB/S001255/1)

  • Margaritis Voliotis
  • Xiao Feng Li
  • Kevin O’Byrne
  • Krasimira Tsaneva-Atanasova

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 procedures performed were approved by the Animal Welfare and Ethical Review Body Committee at King's College London (PP4006193 ) and conducted in accordance with the UK Home Office Regulations.

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Publication history

  1. Received: June 13, 2021
  2. Accepted: November 16, 2021
  3. Accepted Manuscript published: November 17, 2021 (version 1)

Copyright

© 2021, Voliotis 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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