Definition of the hypothalamic GnRH pulse generator in mice.

The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARN) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARN neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARN population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARN neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARN neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARN neurons as the long-elusive hypothalamic pulse generator driving fertility.