Integrating Mechanistic Models to Decode the GnRH Pulse Generator in Female Mice

The gonadotrophin-releasing hormone (GnRH) pulse generator is a critical neural oscillator that governs reproductive function through the pulsatile release of luteinising hormone (LH) and follicle stimulating hormone (FSH). Early electrophysiological studies, notably by Ernst Knobil, identified multiunit activity (MUA) volleys in the mediobasal hypothalamus that aligned with LH pulses, suggesting a neural basis for GnRH pulsatility. Although GnRH neurons exhibit some intrinsic secretory rhythmicity in vitro, their isolated electrophysiological signatures have proven inconsistent. Recent advances, including GCaMP fibre photometry in freely behaving mice, have revealed a precise correlation between episodic GnRH distal processes and LH pulses. However, it is now well established that a neural oscillator comprising hypothalamic kisspeptin neurones co-expressing neurokinin B and dynorphin, collectively termed the KNDy network, represents the core construct of the GnRH pulse generator. Understanding the dynamics of this network and its modulation by external inputs such as stress, metabolic cues, and circadian rhythms is essential. Computational modelling provides a systematic framework for integrating experimental data with mechanistic and predictive analyses to decode the GnRH pulse generator dynamics.