Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome
| Autor: | Chris Coyle, Mauro S.B. Silva, Rebecca Campbell, Elodie Desroziers, Allan E. Herbison, Sabine Hessler, Melanie Prescott |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Research paper Mice Transgenic Hypothalamic–pituitary–gonadal axis Biology General Biochemistry Genetics and Molecular Biology Gonadotropin-Releasing Hormone Mice 03 medical and health sciences 0302 clinical medicine Arcuate nucleus Internal medicine medicine Animals GABAergic Neurons gamma-Aminobutyric Acid GnRH Neuron Luteinizing hormone secretion Ovary Arcuate Nucleus of Hypothalamus Brain General Medicine Luteinizing Hormone Immunohistochemistry Polycystic ovary Disease Models Animal 030104 developmental biology medicine.anatomical_structure Endocrinology nervous system 030220 oncology & carcinogenesis Androgens GABAergic Female Neuron Luteinizing hormone Polycystic Ovary Syndrome |
| Zdroj: | EBioMedicine. 44:582-596 |
| ISSN: | 2352-3964 |
| Popis: | 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 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 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 GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels. Interpretation 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. |
| Databáze: | OpenAIRE |
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