Upstream Regulation of Kiss1 Cells

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Ovulation depends on a surge in the release of luteinizing hormone (LH), which in turn depends on a surge of gonadotropin-releasing hormone (GnRH). In recent years, kisspeptin (KISS) has emerged as the most potent stimulator of GnRH and a key regulator of reproductive development and health in vertebrates, including humans. In females, KISS signaling to GnRH cells is critical for the induction of the LH surge. Despite the central role of KISS in reproduction and specifically in female reproductive development and fertility, little is known about the upstream regulators of neurons expressing Kiss1, the gene coding for KISS. Here we present preliminary results that indicate that Kiss1 expression and the expression of c-fos within Kiss1 neurons in female mice is under circadian regulation, and this regulation is dependent on the presence of high ovarian estrogen levels. The overall goal of this proposal is to determine the pathways by which the circadian system may regulate the activity of Kiss1 neurons. Our laboratory has developed a rat model of circadian desynchronization in which independent circadian outputs are associated with the desynchronized activity of anatomically identifiable subregions of the hypothalamic suprachiasmatic nucleus (SCN), the site of the mammalian master circadian pacemaker. Our preliminary data on this forced desynchronized rat model indicates that the gating of the luteinizing hormone (LH) surge is associated with the activity of the dorsomedial (dm) SCN irrespective of the activity of the ventrolateral (vl) SCN. Because the dmSCN is the main source of vasopressinergic efferent fibers, our hypothesis is that vasopressin (VP) release is a critical SCN signal to induce the LH surge and therefore to activate Kiss1 neurons in a circadian pattern. We propose experiments that test specific predictions of this hypothesis. We will test the prediction that SCN vasopressinergic fibers innervate Kiss1-expressing cells and that innervation of the Kiss1 neuronal network by SCN efferent fibers is critical to sustain the circadian regulation of Kiss1 and of c-fos expression within Kiss1 neurons, which are concomitant with the LH surge. We will use unilateral lesions of the SCN to ipsilaterally deplete the anteroventral periventricular nucleus of SCN efferent fibers. In these animals we will assess the level of asymmetric VP innervation of Kiss1 neurons as well as the asymmetry in the circadian regulation of Kiss1 expression and c-fos expression within Kiss1 cells. Our proposed studies will characterize the pathways and mechanisms by which the activity of the Kiss1 neuronal network is regulated. Specifically, we will determine how a critical component of the mechanisms leading to ovulation such as the circadian system regulates gene expression within Kiss1 cells. Because the activity of these neurons and the release of KISS are essential for normal ovulation, understanding the upstream regulators of Kiss1 neurons will be key to developing therapies to treat disorders of the hypothalamo-pituitary-ovarian axis.