Neural circuits mediating pulsatile and surge GnRH secretion - SUMMARY Fertility in female mammals is critically dependent on both of the two major modes of GnRH release: episodic and surge secretion. Although the importance of episodic GnRH secretion to fertility, and the key role of the hypothalamic arcuate nucleus (ARN), has been recognized for 40 years, the precise identity of neurons responsible for GnRH pulse generation has only become known in the last decade, stemming from the discovery of KNDy neurons, a unique subpopulation of ARC cells that co-express kisspeptin, neurokinin B (NKB), and dynorphin. The original hypothesis proposed that the synchronous firing of KNDy neurons drives GnRH pulses, with kisspeptin being the output signal to GnRH neurons, and NKB and dynorphin acting as start and stop signals for kisspeptin release, respectively. However, there is growing evidence suggesting a more complex organization of the GnRH pulse generator, with non-KNDy ARN neurons that contain Kiss1R playing a functional role in pulse generation, as well as evidence that both KNDy and Kiss1R neurons are important for GnRH surge secretion. We have also identified GABA and glutamate (GLUT) as neurotransmitters in a high percentage of ARN Kiss1R cells Therefore, in this proposal, we will: 1) test the hypothesis that one or both of these ARN Kiss1R subpopulations are critical for normal episodic LH secretion in ewes, and 2) determine the neural circuits by which ARN Kiss1R cells drive the LH surge in sheep, with a focus on GABA and GLUT Kiss1R cells. These studies will use sheep, an animal model in which the neuroendocrine control of reproduction is very similar to humans, ensuring that what we learn about the neural control of GnRH secretion will very likely be applicable for clinical translation to humans. The results of these studies will further refine our knowledge of the neural systems responsible for pulsatile and surge GnRH secretion, and specifically address the novel role of ARN Kiss1R neurons. Importantly, a better understanding of these systems will also be relevant to pathological conditions in humans because dysfunction of the GnRH pulse generator underlies a variety of reproductive disorders including polycystic ovarian syndrome. Alterations in KNDy neurons are thought to play a key role in these disorders, and pharmaceutical agents targeting KNDy peptides and their receptors are currently being explored as new avenues of treatment in clinical trials.
