Circadian Regulation of Gonadotropin-Releasing Hormone

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DESCRIPTION (provided by applicant): Normal mammalian reproduction depends on pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, and ovulation in females requires a robust surge of GnRH. While well known, it is unclear what cellular and molecular mechanisms underlie both modes of peptide release timing. While previous studies implicate 24-hour biological clocks in both mechanisms of reproductive hormone secretion, it is unknown how circadian clocks might act within GnRH neurons to modulate amplitude or frequency of synchronous GnRH secretory release to regulate reproduction. Studies in the previous funding period, using GnRH-secreting GT1-7 cell lines and transgenic mouse models, demonstrated that perturbations in GnRH-specific clocks can modulate secretion, potentially leading to abnormalities in reproduction. Also, preliminary studies described below demonstrate that GnRHspecific clock disruption alters reproductive capacity in vivo, and that endogenous oscillators may play a role in transducing positive feedback effects of estrogen on GnRH neurons, by potentially altering temporal patterns of modulators capable of altering GnRH cell excitability, resulting in neuronal activity changes required for surge release. To investigate this further, the following proposal will 1) evaluate two novel transgenic mouse models to determine the respective contribution of multiple hypothalamic molecular clocks on constructing in vivo GnRH release patterns required for proper reproduction, 2) explore the requirement of endogenous GnRH clocks for estrogen-stimulated surge secretion and changes in neuronal activity, evaluated both in vitro and in vivo, and 3) examine the effects of estrogen on transcriptional regulation of two important neuromodulators, the Kiss-1 receptor GPR54, and the BK ion channel in GnRH neurons in vitro, and explore the involvement of endogenous clocks in these processes. Results from this proposal address fundamental questions about the nature of the GnRH "pulse generator", and how secretion patterns are altered by cell-cell and hormonal communication to produce preovulatory surges. Additionally, these studies provide insight into broader mechanisms of endocrine neurosecretion, and advance circadian biology by exploring how transcriptional oscillations can control synchronous multi-cellular events to regulate numerous biological processes and even orchestrate complex behaviors. Potential applications could lead to new directions in treating a range of reproductive physiological disorders that result from malfunction of hypothalamic neurosecretion, including polycystic ovarian syndrome (PCOS) and primary idiopathic hypogonadism, both of which have been associated with atypical hormone release patterns. PUBLIC HEALTH RELEVANCE: Results generated by this proposal will address fundamental questions about how reproductive neurosecretion patterns are altered by cell-cell communication to produce hormonal surges required for ovulation. Additionally, these studies may advance the circadian biological field by demonstrating how transcriptional oscillations can control synchronous events at the multi-cellular level, to regulate numerous biological processes and even orchestrate complex behaviors. Potential applications could lead to new directions in treating a range of reproductive physiological disorders that result from malfunction of hypothalamic neurosecretion, including polycystic ovarian syndrome (PCOS) and primary idiopathic hypogonadism, both of which have been associated with atypical hormone release patterns.