The Kissl gene encodes peptides called kisspeptins, which bind to a receptor known as GPR54. Kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and Kissl-expressing neurons - which are located in hypothalamic regions that regulate reproduction - and are thought to play a crucial role in the feedback regulation of gonadotropin secretion by gonadal steroids. Although the role of kisspeptin-GPR54 signaling in the steroid control of GnRH secretion has been well-studied, the role of Kissl neurons in the environmental regulation of reproduction is unknown. The goal of this research is to elucidate the physiological role of the Kissl system in the circadian and photoperiodic control of GnRH secretion using the hamster as a model. The first main objective is to evaluate the role of the Kissl system in the circadian-controlled pre-ovulatory LH surge. I will investigate whether Kissl neurons undergo circadian activation in association with the generation of daily LH surges. I will also determine if there are direct neural connections between the circadian oscillator in the suprachiasmatic nucleus (SON) and Kissl neurons, and identify the neurotransmitters involved in this circuitry. The second main objective is to evaluate the role of Kissl in the seasonal control of reproduction. I will assess the affects of photoperiod/melatonin (MEL) on the hypothalamic Kissl system and ascertain whether MEL's affects on Kissl neurons are direct or indirect. I will also comprehensively evaluate the roles of the SON and other nuclei in mediating any indirect effects. Lastly, I will investigate the effects of photoperiod on both the innervation of GnRH neurons by Kissl axons and the sensitivity of Kissl neurons to feedback effects of sex steroids. Since humans exhibit well-documented circadian rhythms in physiology and behavior (including critical aspects of reproduction), as well as seasonal traits (such as Seasonal Affective Disorder), increased knowledge of Kissl involvement in circadian and photoperiodic processes could improve our understanding of the regulation of fertility and facilitate the development of improved medical strategies for human behavioral disorders. In addition, elucidating the role of kisspeptins in the regulation of GnRH secretion could offer further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism and provide the scientific rationale for potential new therapies to treat precocious or delayed puberty, menstrual cycle irregularities, and infertility. ? ? ? ?
| Kauffman, Alexander S; Navarro, Víctor M; Kim, Joshua et al. (2009) Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty. Am J Physiol Endocrinol Metab 297:E1212-21 |
| Kauffman, Alexander S (2009) Sexual differentiation and the Kiss1 system: hormonal and developmental considerations. Peptides 30:83-93 |
| Robertson, Jessica L; Clifton, Donald K; de la Iglesia, Horacio O et al. (2009) Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. Endocrinology 150:3664-71 |
| Roseweir, Antonia K; Kauffman, Alexander S; Smith, Jeremy T et al. (2009) Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29:3920-9 |
