Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome.
Androgens
/ metabolism
Animals
Arcuate Nucleus of Hypothalamus
/ metabolism
Brain
/ metabolism
Disease Models, Animal
Female
GABAergic Neurons
/ metabolism
Gonadotropin-Releasing Hormone
/ metabolism
Immunohistochemistry
Luteinizing Hormone
/ biosynthesis
Mice
Mice, Transgenic
Ovary
/ metabolism
Polycystic Ovary Syndrome
/ etiology
gamma-Aminobutyric Acid
/ metabolism
Chemogenetics
GnRH neurons
Luteinizing hormone
Mouse
Optogenetics
PCOS
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jun 2019
Jun 2019
Historique:
received:
15
03
2019
revised:
26
05
2019
accepted:
30
05
2019
pubmed:
11
6
2019
medline:
18
12
2019
entrez:
11
6
2019
Statut:
ppublish
Résumé
Enhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined. We employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features. Acute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABA ARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.
Sections du résumé
BACKGROUND
BACKGROUND
Enhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined.
METHODS
METHODS
We employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features.
FINDINGS
RESULTS
Acute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABA
INTERPRETATION
CONCLUSIONS
ARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.
Identifiants
pubmed: 31178425
pii: S2352-3964(19)30373-1
doi: 10.1016/j.ebiom.2019.05.065
pmc: PMC6606966
pii:
doi:
Substances chimiques
Androgens
0
Gonadotropin-Releasing Hormone
33515-09-2
gamma-Aminobutyric Acid
56-12-2
Luteinizing Hormone
9002-67-9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
582-596Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.