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Gene Expression Patterns in the Preoptic Area of Mice with Defective FGF Signaling in GnRH Neurons

ABSTRACT: Sexual interactions have previously been shown to improve reproductive health through unknown mechanisms. In this study, we used RNA-Seq to examine sex-induced gene expression changes in the preoptic area (POA), a critical reproductive brain region. Using a mouse model defective in fibroblast growth factor signaling (dnFGFR mouse), previously shown to disrupt the gonadotropin-releasing hormone (GnRH) system, we examined the impact of opposite sex (OS) housing on gene expression in the POA of a reproductively compromised animal. Bulk RNA-Seq followed by gene set enrichment analysis (GSEA) were used to analyze changes in gene expression and biological processes in control and dnFGFR mice after 300 days of cohabitation with a same sex or OS partner. OS housing of dnFGFR mice, but not control mice, significantly improved reproductive anatomy and gonadotropins in dnFGFR mice. These changes occurred concomitantly with novel biological processes related to estradiol metabolism and neuron excitation. Our results suggest a new role of neuron- or astrocyte-derived estradiol in the plasticity of the GnRH neuron population and offer a promising new direction for the treatment of reproductive disorders stemming from GnRH deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE285006 | GEO | 2025/02/28

REPOSITORIES: GEO

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Project description:Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

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Gene Expression Patterns in the Preoptic Area of Mice with Defective FGF Signaling in GnRH Neurons

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