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

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.

Reviewing Editor

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

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.

Version history

  1. Preprint posted: March 22, 2021 (view preprint)
  2. Received: June 13, 2021
  3. Accepted: November 16, 2021
  4. Accepted Manuscript published: November 17, 2021 (version 1)
  5. Version of Record published: December 7, 2021 (version 2)

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.

Metrics

  • 923
    views
  • 212
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Margaritis Voliotis
  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
(2021)
Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network
eLife 10:e71252.
https://doi.org/10.7554/eLife.71252

Share this article

https://doi.org/10.7554/eLife.71252

Further reading

    1. Neuroscience
    Songyao Zhang, Tuo Zhang ... Tianming Liu
    Research Article

    Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.

    1. Neuroscience
    Avani Koparkar, Timothy L Warren ... Lena Veit
    Research Article

    Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.