Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network

• DOI: 10.7554/elife.71252
• Publication Date: 2021-11-17T13:00:14Z
• Authors: Margaritis Voliotis; Xiao Feng Li; Ross Alexander De...; Geffen Lass; Deyana Ivanova; Caitlin McIntyre; Kevin O'Byrne; Krasimira Tsaneva...
• Keywords: Kisspeptin; Neurokinin B; Dynorphin; Pulsatile flow

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy co-expressing neurokinin B, and dynorphin, drive pulsatile release. Furthermore, gonadal steroids regulate dynamics across ovarian cycle by altering neurons' signalling properties. However, precise mechanism of regulation remains mostly unknown. To better understand these mechanisms, we start perturbing system at different stages estrous using optogenetics. We find that optogenetic stimulation stimulates GnRH/LH secretion mice but inhibits it diestrous mice. These vivo results combination with mathematical modelling suggest transition between estrus diestrus underpinned well-orchestrated changes neuropeptide excitability population controlled via glutamate signalling. Guided model predictions, show blocking animals LH pulses, optic mitigates this inhibition. In mice, disruption pulses generated sustained low-frequency population, supporting idea level network critical pulse generation. Our reconcile previous puzzling findings regarding estradiol-dependent effect several neuromodulators have on generator dynamics. Therefore, anticipate our to be a cornerstone more quantitative understanding pathways which Finally, could inform useful repurposing drugs targeting therapy.