SUN-245 Sensory Neuron Metabolism Mediates Changes in Ovarian Function via LKB1

Abstract

Bi-directional communication between sensory neurons to peripheral tissue to mediate physiology has become an area of interest. Previous research on peripheral neuron control of ovarian function shows that lesioning the superior ovarian nerve resulted in decreased estradiol release from the ovary; but there has been little research on how sensory neurons affect ovarian physiology. Interestingly, the metabolic activity of sensory neurons that control ovarian and follicular function may have profound effects on tissues they innervate. LKB1 (Liver Kinase B1) is a metabolic kinase that regulates cell growth and polarity. When downregulated in cortical neurons in vitro, leads to shorter axons with less branching. Female mice with LKB1 removed from their peripheral sensory neurons have litters more often and increased litter sizes compared to wild-type mice, which led to the investigation into the mechanisms into the role of LKB1 in sensory neurons in ovarian function. Nav1.8cre-LKB1fl/fl mice were used to assess the removal of LKB1 from Nav1.8-expressing neurons on the mechanisms behind reproductive viability. The estrus cycle was tracked by using vaginal lavage to collect cells from the vagina twice per day for ten days, and cytology was assessed to determine phase. Ovaries were collected from mice in all phases of the estrus cycle, sectioned at 8 micron thickness, stained with H&E. Follicle sizes and numbers were measured on 8 sections per ovary. Sensory innervation was measured by clearing whole ovary using ScaleS1 and using confocal microscopy to image through the whole tissue for sensory neurons tagged with tdTomato and DAPI. Our data indicate that Nav1.8-expressing neurons innervate the ovary from celiac ganglia, upper lumbar, and lower thoracic dorsal root ganglia. Nav1.8cre-LKB1fl/fl mice have larger litters and breed more frequently compared to cre-negative litter mates (WT). Nav1.8cre-LKB1fl/fl mice have larger ovaries, spend less time in proestrus, and have greater follicular turnover compared to WT mice. Phase-matched ovaries from Nav1.8cre-LKB1fl/fl mice in proestrus show greater numbers of antral and degenerating follicles than WT mice, but similar numbers of immature follicles; however, the size of all follicles from Nav1.8cre-LKB1fl/fl mice are smaller than follicles from WT mice. Nav1.8cre-LKB1fl/fl mice have improved reproductive viability by increased follicular turnover rate, more mature follicles, and shortened estrus cycle length.