Abstract
Reproduction critically depends on the pulsatile secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamus. This ultradian rhythm drives the secretion of gonadotrophic hormones (LH and FSH) from the pituitary gland, which are critical for gametogenesis and ovulation, and its frequency is regulated throughout the life course to maintain normal reproductive health. However, the precise mechanisms controlling the pulsatile GnRH dynamics are unknown. Here, we propose and study a novel mathematical model of a population of neurones in the arcuate nucleus (ARC) of the hypothalamus that co-expresses three key modulators of GnRH secretion: kisspeptin; neurokinin B (NKB); and dynorphin (Dyn). The model highlights that positive feedback in the population exerted by NKB and negative feedback mediated by Dyn are the two key components of the pulse generator, which operates as a relaxation oscillator. Furthermore, we use the model to study how external inputs modulate the frequency of the pulse generator, a prediction that can be readily tested in-vivo using optogenetically-driven stimulation. Finally, our model predicts the response of the system to various neuropharmacological perturbations and reconciles inconsistent experimental observations following such interventions in-vivo. We anticipate that our model in combination with cutting-edge, in-vivo techniques, allowing for neuronal stimulation and recording, will set the stage for a quantitative, system-level understanding of the GnRH pulse generator.
Footnotes
↵* M.Voliotis{at}exeter.ac.uk, K.Tsaneva-Atanasova{at}exeter.ac.uk