SAT-010 Alpha-MSH Regulation Of GnRH Neuronal Activity Over Development: Dramatic Changes In Proestrus Females

Abstract Disclosure: N. da Silva Mansano: None. S. Wray: None. Gonadotropin-releasing hormone (GnRH) neurons are essential for fertility, integrating external and internal signals such as metabolic status, to ensure reproductive success. Both overweight and underweight individuals, in rodents and humans, can exhibit reproductive dysfunctions. GnRH neurons express receptors for the anorexigenic proopiomelanocortin, as well as its product, α-melanocyte-stimulating hormone (α-MSH). This suggests a direct link between metabolic function and reproduction. However, how these circuit might interact over development is unclear. To investigate the relationship between α-MSH and GnRH neurons electrophysiology loose-patch clamp recordings of brain slices from prepubertal, pubertal, and adult GnRH-GFP mice were performed in male and female, including 3 stages of the estrous cycle (diestrus, estrus and proestrus). In males and females, α-MSH excited GnRH neurons in prepubertal and pubertal mice. In adult males, most GnRH neurons show no change in activity by α-MSH, while females in either estrus or diestrus show excitation, as detected in younger mice. Notably, in proestrus females a significant inhibition is recorded in GnRH neurons with application of α-MSH. Double labeling for GnRH and α-MSH revealed α-MSH fibers closely juxtaposed to GnRH neurons at all stages. The inhibition observed in proestrus females suggested a third player in this circuit. Inhibition in females during proestrus was found to be via α-MSH activation of nocioceptin/orphanin FQ (OFQ) inhibitory afferents to GnRH neurons, mediated via opioid receptor-like receptor-1 (ORL-1s). OFQ is known to regulate feeding, increasing food intake via circuits in the arcuate nucleus. However, OFQ also suppresses GnRH neuronal activity, GnRH and LH release. Our results indicate that α-MSH modulates GnRH neuronal activity in a developmental specific manner and that during the LH surge, a time of active mating, metabolic cues can be inhibited on GnRH neurons via the nociception system. Together, these data emphasized a circuit between GnRH neurons, the melanocortin system and the nociception system, linking energy balance and reproduction. Presentation: Saturday, July 12, 2025