The Kissi gene encodes proteins called kisspeptins, v^rhich bind to the G-protein coupled receptor GPR54. Kissl is expressed in discrete brain regions that regulate reproductioa and in mammals, induding humans, kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins (LH, FSH). Kissl neurons are themselves regulated by gonadal sex hormones, suggesting a crucial role for kisspeptin signaling in the negative and positive feedback regulation of reproduction. Although the stimulatory role of kisspeptin-GPR54 signaling in the control of GnRH secretion has been well-studied, the role of Kissl nemons in the environmental, circadian, and developmental regulation of reproductioivis much less cftaractenzea. ine goals or this research are to elucidate the physiological role Ofthe KiHlil system in the circadian, photoperiodic, and developmental control of GnRH secretion. The first objective is to evaluate the role of Kissl neurons in the drcadian-controlled pre-ovulatory LH surge. In females, the pre-ovulatory LH surge is coupled to a circadian oscillator in the suprachiasmatic nucleus (SCN). Althoiigh the rieural circuitry and neuroendocrine factors that mediate the SCN's control of the surge remain unidentified, evidence implicates the involvement of Kissl neurons. I will investigate whether Kissl neurons undergo circadian activation at the time of daily LH surges and determine whether there are direct neural cormections between the SCN and Kissl neurons (and if so, identify"""""""" the neurotransmitters involved in this circuitry). The second main objective is to evaluate the role of Kissl neurons in the seasonal control of reproduction and sexual maturation. It is known that seasoital reproduction and puberty onset are governed by pineal melatonin (MEL) secretion (which reflects day length), but the neural circuitry that integrates and relays MEL signals to GnRH neurons remains unidentified. I wiU assess the effects of photoperiod/MEL on the hypothalamic Kissl system, ascertain whether MEL's effects on Kissl neurons are direct or indirect, and determine how the regulation of Kissl neurons varies with developmental status (puberty). I will also comprehensively evaluate the roles of several candidate nuclei in relaying any indirect effects of MEL on Kissl neurons. Lastly, I will investigate how the irmervatipn of GnRH neurons by Kissl axons and the sensitivity oi Kissl neurons to feedback effects of sex steroids areregulated by photoperiod and developmental status.
Elucidating the role of Kissl neurons in the regulation of GnRH secretion in mammals could offer further insight into the neural and endocrine mechanisms responsible for idiopathic hypogonadotropic hypogonadism in humans and could provide the sdentific rationale for potential new therapies to treat precocious or delayed puberty, menstrual cyde irregularities, infertility, and other reproductive and sexual disorders.
