Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network.
GnRH pulse generator
KNDy
mathematical model
mouse
neuroscience
optogenetics
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
17 11 2021
17 11 2021
Historique:
received:
13
06
2021
accepted:
16
11
2021
pubmed:
18
11
2021
medline:
22
1
2022
entrez:
17
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34787076
doi: 10.7554/eLife.71252
pii: 71252
pmc: PMC8651288
doi:
pii:
Substances chimiques
Kisspeptins
0
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S000550/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S001255/1
Pays : United Kingdom
Informations de copyright
© 2021, Voliotis et al.
Déclaration de conflit d'intérêts
MV, XL, RD, GL, DI, CM, KO, KT No competing interests declared
Références
Elife. 2016 Aug 23;5:
pubmed: 27549338
Eur J Pharmacol. 1995 Jan 24;273(1-2):113-9
pubmed: 7537676
J Neuroendocrinol. 1994 Oct;6(5):557-64
pubmed: 7827626
Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6736-40
pubmed: 8393575
Endocrinology. 2015 Jul;156(7):2582-94
pubmed: 25856430
Neuroendocrinology. 1993 Apr;57(4):710-5
pubmed: 7690119
Neurosci Lett. 2016 Jan 26;612:161-166
pubmed: 26679227
J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):847-50
pubmed: 1348628
Endocrinology. 2016 Dec;157(12):4794-4802
pubmed: 27715255
Brain Res. 2004 Nov 12;1026(2):307-12
pubmed: 15488494
J R Soc Interface. 2009 Feb 6;6(31):187-202
pubmed: 19205079
Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E202-10
pubmed: 21045176
Neuroendocrinology. 1991 Oct;54(4):405-11
pubmed: 1758582
Elife. 2018 Aug 06;7:
pubmed: 30079889
Endocr Rev. 2010 Aug;31(4):544-77
pubmed: 20237240
J Neurosci. 2009 Sep 23;29(38):11859-66
pubmed: 19776272
Mol Endocrinol. 2016 Jun;30(6):630-44
pubmed: 27093227
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13109-14
pubmed: 26443858
Endocrinology. 2019 Jun 1;160(6):1480-1491
pubmed: 31083714
J Neuroendocrinol. 2016 Nov;28(11):
pubmed: 27663274
J Neurosci. 2019 Dec 4;39(49):9738-9747
pubmed: 31645462
Endocrinology. 2018 Sep 1;159(9):3219-3234
pubmed: 30010844
Neuroendocrinology. 2020;110(3-4):172-184
pubmed: 31466075
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11891-6
pubmed: 15280536
Endocrinology. 2012 Jan;153(1):307-15
pubmed: 22109887
Exp Physiol. 2013 Nov;98(11):1535-43
pubmed: 23884368
Endocrinology. 1991 Sep;129(3):1207-14
pubmed: 1874166
J Neuroendocrinol. 2015 Jul;27(7):624-35
pubmed: 25976424
J Physiol. 1979 May;290(2):433-40
pubmed: 469785
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10978-83
pubmed: 9724815
Endocrinology. 2011 Sep;152(9):3451-60
pubmed: 21693677
J Neuroendocrinol. 2020 Feb;32(2):e12823
pubmed: 31872920
Endocr Rev. 1983 Fall;4(4):311-51
pubmed: 6360674
Endocrinology. 2016 Feb;157(2):752-63
pubmed: 26562263
Neuroscience. 2011 Jan 26;173:37-56
pubmed: 21093546
Endocrinology. 2011 Apr;152(4):1503-14
pubmed: 21285322
J Neurosci. 2018 Jan 31;38(5):1061-1072
pubmed: 29114074
Endocrinology. 2017 Oct 1;158(10):3553-3564
pubmed: 28938398
PLoS One. 2012;7(7):e39001
pubmed: 22802933
Endocrinology. 1990 Aug;127(2):724-9
pubmed: 2197080
Endocrinology. 2013 Dec;154(12):4939-45
pubmed: 24092638