The peptidergic control circuit for ovarian cycles

The female reproductive cycle is a fundamental physiological process that determines fertility, sexuality, and mood. The regularity of reproductive cycles is closely regulated by neuropeptide- and hormone-mediated communication between neurons in the hypothalamus of the brain and the ovaries. Despite extensive research on the top-down control (hypothalamus-pituitary-ovarian axis, HPO), the precise neuronal targets of ovarian hormonal feedback are not well understood. Gonadotrophin-releasing hormone (GnRH) neurons, the master regulator of the HPO axis, switch between pulsatile and surge release modes to control ovulation and ovarian hormone release. Using quantitative in situ hybridisation, single cell RNA sequencing, we discover a novel peptidergic cell type in the medial preoptic nucleus of the rat brain. This cell type expresses both estrogen and progesterone receptors, similar to kisspeptin neurons. Cell type specific abalation results in arrest of the reproductive cycle and aestrus in female rats. Anatomical and electrophysiological evidence suggests that GnRH neurons are directly activated by this cell type. This activation allows GnRH to switch from a pulsatile to a surge release mode. These findings extend the current model of ovarian steroid feedback signalling on GnRH neurons and highlight the effects of progesterone beyond pregnancy. This hormone- and neuropeptide-dependent hub highlights the power of cyclically changing ovarian hormones during the female reproductive cycle in maintaining ovarian health.