Shifting GnRH neuron ensembles underlie successive preovulatory luteinizing hormone surges

The gonadotropin-releasing hormone (GnRH) neurons operate as a neuronal ensemble exhibiting coordinated activity once every reproductive cycle to generate the preovulatory GnRH surge. Using GCaMP fibre photometry at the GnRH neuron distal dendrons to measure the output of this widely scattered population in female mice, we find that the onset, amplitude, and profile of GnRH neuron surge activity exhibits substantial variability from cycle to cycle both between and within individual mice. This was also evident when measuring successive proestrous luteinizing hormone surges. Studies combining short (c-Fos and c-Jun) and long (genetic Robust Activity Marking) term indices of immediate early gene activation revealed that, while ∼50% of GnRH neurons were activated at the time of each surge, only half of these neurons had been active during the previous proestrous surge. These observations reveal marked inter- and intra-individual variability in the GnRH surge mechanism. Remarkably, different sub-populations of overlapping GnRH neurons are recruited to the ensemble each estrous cycle to generate the GnRH surge. While engendering variability in the surge mechanism itself, this likely provides substantial robustness to a key event underlying mammalian reproduction.Significance Statement The mid-cycle luteinizing hormone (LH) surge driven by the gonadotropin-releasing hormone (GnRH) neurons represents the key event triggering ovulation in all mammals. Using GCaMP fibre photometry and genetic activation markers, we unexpectedly find that different sub-populations of GnRH neurons are responsible for driving consecutive LH surges every 4-5 days in cycling female mice. This remarkable oscillatory pattern of network plasticity within the ensemble occurs under normal physiological conditions and likely contributes to the variable timing of the onset of LH surge both within and between individuals. The ability of individual GnRH neurons to take turns within the ensemble in driving the LH surge likely provides a robust fail-safe mechanism for ovulation and contributes to the robustness of mammalian fertility.