GnRH Pulse Generator Activity Across the Estrous Cycle of Female Mice

A subpopulation of kisspeptin neurons located in the arcuate nucleus (ARN) operate as the GnRH pulse generator. The activity of this population of neurons can be monitored in real-time for long periods using kisspeptin neuron-selective GCaMP6 fiber photometry. Using this approach, we find that ARN kisspeptin neurons exhibit brief (∼50 seconds) periods of synchronized activity that precede pulses of LH in intact female mice. The dynamics and frequency of these synchronization episodes (SEs) are stable at approximately one event every 40 minutes throughout metestrus, diestrus, and proestrus, but slow considerably on estrus to occur approximately once every 10 hours. Evaluation of ARN kisspeptin neuron activity across the light-dark transition, including the time of onset of the proestrus LH surge, revealed no changes in SE frequency. Longer 24-hour recordings across proestrus into estrus demonstrated that an abrupt decrease in SEs occurred ∼4 to 5 hours after the onset of the LH surge to reach the low frequency of SEs observed on estrus. The frequency of SEs was stable across the 24-hour period from metestrus to diestrus. Administration of progesterone to diestrus mice resulted in the abrupt slowing of SEs. These observations show that the GnRH pulse generator exhibits an unvarying pattern of activity from metestrus through to the late evening of proestrus, at which time it slows dramatically, likely in response to postovulation progesterone secretion. The GnRH pulse generator maintains a constant frequency of activity across the time of the LH surge, demonstrating that it is not involved directly in surge generation.