Function and Molecular Phenotyping of Amygdala Kisspeptin Neurons

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 DESCRIPTION (provided by applicant): The neuropeptide kisspeptin, encoded by the Kiss1 gene, activates reproduction by signaling directly to GnRH neurons through the kisspeptin receptor (Kiss1r). Kiss1/kisspeptin cells are detected in several brain regions, primarily the hypothalamic anteroventral periventricular nucleus (preoptic area in primates and sheep), the hypothalamic arcuate nucleus, and the amygdala, but the regulation and function of kisspeptin in the amygdala has received very little attention. The medial amygdala (MeA) is an estradiol-sensitive region implicated in modulating reproductive endocrinology and behavior, but the mechanism(s) by which the MeA influences reproduction, and if these mechanisms are similar between males and females, remain unknown. In addition, the MeA is also important for the discrimination and modulation of olfactory information on aspects of reproductive physiology and behavior, with MeA neurons discriminating and selectively responding to opposite- sex odors. However, the identity of the specific MeA cell types involved and the mechanisms by which this occurs are still poorly understood. Given that kisspeptin treatment alters reproductive physiology and that kisspeptin signaling is required for opposite-sex odor preference, it is possible that kisspeptin neurons in the MeA play an important role in these specific reproductive events. The overall goal of this project is to examine the regulation and reproductive function of Kiss1 neurons in the MeA, of which virtually nothing is known at present. Aim 1 examines the neuroanatomical projections of MeA Kiss1 neurons to determine whether MeA Kiss1 neurons directly project to GnRH neurons, thus having the potential to directly influence reproduction, and whether MeA Kiss1 efferent projections are similar in males and females. Aim 2 directly examines the possibility for reproductive function of Kiss1 neurons in the MeA, as well as the influence of Kiss1 neurons in the MeA on opposite-sex odor preference. In addition, Aim 2 explores whether potential functions of Kiss1 neurons in the MeA are similar for males and females. Aim 3 will determine what genes are actively expressed by MeA Kiss1 neurons, whether this molecular phenotype is E2 dependent, and if the genes expressed by MeA Kiss1 neurons differ between males and females, all of which will provide novel and fundamental insight into the regulation and potential functions of these particular Kiss1 neurons. In addition o modulating reproduction, the MeA mediates various behaviors such as stress, anxiety, and social behavior, and the proposed research will not only determine the role of MeA Kiss1 neurons in regulating reproduction, but will also provide a basis to further explore potential non-reproductive functions of MeA Kiss1 neurons. Overall, this work may provide important information relevant to treatments in infertility, anovulation, amenorrhea, and idiopathic hypogonadotropic hypogonadism, as well as improve our understanding of reproductive physiology regulation in disorders associated with aberrant amygdala function.