Neuronal networks that regulate gonadotropin-releasing hormone/luteinizing hormone secretion during undernutrition: evidence from sheep.

Gonadotropin-releasing hormone (GnRH) neurons are the final common conduit from the central nervous system in the reproductive axis, controlling luteinizing hormone (LH) secretion from the gonadotropes of the anterior pituitary. Although it is generally accepted that undernutrition inhibits GnRH/LH secretion, the central mechanisms that underlie the link between energy balance and reproduction remain to be fully elucidated. Sheep have been a longstanding and invaluable animal model for examination of the nutritional regulation of GnRH/LH secretion, given their ability to serve a biomedical and agricultural purpose. In this review, we summarize work that has used the ovine model to examine the central mechanisms whereby undernutrition regulates GnRH/LH secretion. Specifically, we focus our attention to the arcuate nucleus of the hypothalamus and on neurons that express kisspeptin, neurokinin B, dynorphin, proopiomelanocortin, and neuropeptide y/agouti-related peptide (NPY/AgRP). We examine their roles in mediating the effects of leptin and insulin and their effects on LH during undernutrition, as well as their regulation under conditions of undernutrition. This review will also highlight the interactions between the aforementioned neuronal networks themselves, which may be important for our understanding of the roles each play in relaying information regarding energy status during times of undernutrition to ultimately regulate GnRH/LH secretion.

Evidence for Changes in Numbers of Synaptic Inputs onto KNDy and GnRH Neurones during the Preovulatory LH Surge in the Ewe.

Kisspeptin neurones located in the arcuate nucleus (ARC) and preoptic area (POA) are critical mediators of gonadal steroid feedback onto gonadotrophin-releasing hormone (GnRH) neurones. ARC kisspeptin cells that co-localise neurokinin B (NKB) and dynorphin (Dyn), are collectively referred to as KNDy (Kisspeptin/NKB/Dyn) neurones, and have been shown in mice to also co-express the vesicular glutamate transporter, vGlut2, an established glutamatergic marker. The ARC in rodents has long been known as a site of hormone-induced neuroplasticity, and changes in synaptic inputs to ARC neurones in rodents occur over the oestrous cycle. Based on this evidence, the the present study aimed to examine possible changes across the ovine oestrous cycle in synaptic inputs onto kisspeptin cells in the ARC (KNDy) and POA, and inputs onto GnRH neurones. Gonadal-intact breeding season ewes were perfused using 4% paraformaldehyde during either the luteal or follicular phase of the oestrous cycle, with the latter group killed at the time of the luteinising hormone (LH) surge. Hypothalamic sections were processed for triple-label immunodetection of kisspeptin/vGlut2/synaptophysin or kisspeptin/vGlut2/GnRH. The total numbers of synaptophysin- and vGlut2-positive inputs to ARC KNDy neurones were significantly increased at the time of the LH surge compared to the luteal phase; because these did not contain kisspeptin, they do not arise from KNDy neurones. By contrast to the ARC, the total number of synaptophysin-positive inputs onto POA kisspeptin neurones did not differ between luteal phase and surge animals. The total number of kisspeptin and vGlut2 inputs onto GnRH neurones in the mediobasal hypothalamus (MBH) was also increased during the LH surge, and could be attributed to an increase in the number of KNDy (double-labelled kisspeptin + vGlut2) inputs. Taken together, these results provide novel evidence of synaptic plasticity at the level of inputs onto KNDy and GnRH neurones during the ovine oestrous cycle. Such changes may contribute to the generation of the preovulatory GnRH/LH surge.