Abstract
Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodeling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One-third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPYARN) of ARN GABA neurons (GABAARN) is also affected in prenatally androgenized (PNA) PCOS-like NPYARN reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPYARN neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPYARN neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPYARN neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPYARN neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPYARN neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPYARN neurons are not remodeled by prenatal androgen excess like the wider GABAARN population, indicating GABA-to-GnRH neuron circuit remodeling occurs in a presently unidentified non-NPY/AgRP population of GABAARN neurons. NPYARN neurons do, however, show independent changes in the form of elevated androgen sensitivity.
Highlights
Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion
The present study assessed the impact of prenatal androgen excess, which models PCOS features, on the NPYARN-toGnRH neuron circuit
Confocal analysis of close appositions between NPYARN neurons fibers and GnRH neurons found no differences in the NPYARN-to-GnRH neuron projection in PCOS-like prenatally androgenized (PNA) females
Summary
Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Androgenized (PNA) mice, which reflect the cardinal features and neuroendocrine impairments of PCOS [20], display a greater frequency of GABAergic postsynaptic currents in GnRH neurons [13, 15] and elevated GnRH neuron firing frequency [15, 19, 21] compared with fertile controls This is associated with a greater number of closely associated presynaptic GABAergic terminals and a dramatically increased projection of GABAergic fibers from the arcuate nucleus (ARN) [14]. Given that elevated GABAARN input is largely to the proximal dendrite of GnRH neurons in PCOS-like animals [12, 14] and the high degree of NPY co-expression in GABAARN neurons [31], we aimed to investigate whether the NPY/ AgRP-specific subpopulation of GABAARN neurons is remodeled in the PNA mouse model of PCOS This was achieved using transgenic AgRP-Cre;τGFP reporter mice to visualize NPYARN cell bodies and fiber projections. We hypothesized that the NPYARN-to-GnRH neuron circuit and the steroid hormone sensitivity of NPYARN neurons would be impacted in PNA-induced PCOS-like mice
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