Definition of the hypothalamic GnRH pulse generator in mice.

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Clarkson, Jenny 
Han, Su Young 
Piet, Richard 
McLennan, Timothy 
Kane, Grace M 

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 (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARNKISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARNKISS 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 ARNKISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARNKISS neurons as the long-elusive hypothalamic pulse generator driving fertility.

GnRH, arcuate nucleus, fertility, kisspeptin, pulse, Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Female, Gonadotropin-Releasing Hormone, Kisspeptins, Luteinizing Hormone, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neurons, Optogenetics, Periodicity, Photometry, Voltage-Sensitive Dye Imaging
Journal Title
Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
Biotechnology and Biological Sciences Research Council (BB/K003178/1)
Isaac Newton Trust (1540(h))