The role of AVPV Kiss1 neurons in modulating female and male reproduction - PROJECT SUMMARY About 10% of couples in the United States suffer from infertility, but infertility is multi-faceted and many causes of infertility remain unknown. Currently, the treatments for infertility are quite expensive and are not always successful, averaging a 3-30% success rate depending on the woman’s age. Thus, understanding the brain’s role in regulating fertility and reproductive physiology will be imperative to developing new and more efficient treatments. Reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis, but despite much research, the mechanisms that modulate the HPG axis are not fully understood. The neuropeptide kisspeptin, encoded by the Kiss1 gene, is essential for reproduction, with mutations in Kiss1 or Kiss1r, the kisspeptin receptor, resulting in severe deficits in reproductive hormone release, and fertility. Kisspeptin stimulates the reproductive axis by stimulating GnRH neurons. Kisspeptin or Kiss1 expression is found in multiple brain areas, in the hypothalamus in the anteroventral periventricular (AVPV)/periventricular (PeN) nuclei and the arcuate (ARC) nucleus, as well as outside the hypothalamus, in the medial amygdala, bed nucleus of the stria terminalis, and lateral septum. Kiss1 neurons in the AVPV/PeN are hypothesized to be involved in estradiol (E2)-mediated positive feedback and the LH surge in females because Kiss1 expression in the AVPV increases with E2 treatment and females express more Kiss1 in this region than do males. In further support of this hypothesis, AVPV Kiss1 neurons show increased neuronal activation exclusively during the LH surge and Kiss1 KO and Kiss1r KO mice cannot exhibit an LH surge even with exogenous E2 treatment. However, it remains unknown whether Kiss1 neurons in the AVPV are required for the LH surge, regular ovarian cycles, and fertility in females. In addition, because of the prominent sex difference in Kiss1 mRNA expression, with females expressing more Kiss1 mRNA than do males, the function of this population of Kiss1 neurons in males remains unexplored, despite findings that males do express Kiss1 in the AVPV. This proposal examines the necessity of AVPV Kiss1 neurons in modulating fertility and reproductive physiology in both males and females. Recent data examining the molecular phenotype of AVPV Kiss1 neurons demonstrated these cells produce over 12,000 different transcripts with over 600 transcripts differentially regulated by E2 treatment. However, it remains unknown which of these transcripts may be increased specifically during the LH surge and what gene transcripts differ between sexes and across development. Therefore, this proposal will also examine sex and age-related differences in the molecular phenotype of AVPV Kiss1 cells and identify which transcripts are specifically increased during the LH surge in females. These experiments may provide important novel information relevant to treatments for infertility, anovulation, amenorrhea, and idiopathic hypogonadotropic hypogonadism, as well as understanding how reproduction and reproductive disorders may differ between males and females.
