The overall goal of our laboratory's research is to determine the cellular and molecular mechanisms underlying episodic gonadotropin-releasing hormone (GnRH) secretion, as well as to understand the role of GnRH in the presentation of various forms of hypothalamic infertility. GnRH neurons form the final common pathway for the central regulation of reproduction in all vertebrates. GnRH is released in a pulsatile pattern that is critical for release of gonadotropic hormones by the pituitary gland. Further, the frequency of GnRH release changes throughout the female reproductive cycle and these changes are prerequisite for shifting the relative levels of the two gonadotropins to allow for ovarian follicular development and maturation. Persistence of high frequency GnRH release is a hallmark of hyperandrogenic polycystic ovary syndrome (PCOS, recently renamed MORS, metabolic ovarian reproductive syndrome), which affects approximately 8% of women and is a major cause of infertility and other health problems, including diabetes and obesity. To study this system we use transgenic mouse models in which the jellyfish reporter green fluorescent protein (GFP) is genetically targeted to GnRH neurons or other neurons in the brain that are important for controlling GnRH neurons, such as those that produce kisspeptin. These mice enable us to identify living neurons in brain slices and study them using electrophysiological, imaging and molecular approaches. Our work on PCOS has examined the interface between metabolic perturbations and fertility, specifically testing how GnRH neurons sense energy availability. In vivo, we have examined the effects of high fat diet, fasting, and metformin therapy on fertility. Ongoing and future work is testing the effect of voluntary exercise (running wheels) on reproductive parameters and metabolic parameters. For the latter, the Animal Phenotyping Core provides essential expertise that allows us to examine mechanistic aspects that are beyond the capabilities of our own laboratory. Collaborations with fellow NORC members Carol Elias and Martin Myers on how metabolic cues are conveyed to the GnRH neuron have enriched our understanding of this system.