UC Berkeley

In spontaneously-ovulating rodents, signaling from the suprachiasmatic nucleus (SCN) integrates with high ovarian estradiol concentrations secreted from mature ovarian follicles to stimulate the preovulatory luteinizing hormone (LH) surge that initiates ovulation. Although the requirement for SCN signaling in the initiation of the LH surge is well established, the neurochemical identity of SCN cells participating in the surge, their target loci, and their specific mechanisms of action remain to be fully determined. Kisspeptin- and RFamide related peptide-3 (RFRP-3)-expressing neurons that lie upstream of the gonadotropin-releasing hormone (GnRH) system positively and negatively drive reproductive axis activity, respectively. Several lines of evidence point to a potential role for vasoactive-intestinal polypeptide (VIP) -ergic and arginine vasopressin (AVP) -ergic SCN cells in coordinating the timing of the LH surge through direct and indirect actions on the kisspeptin and RFRP-3 systems. The overarching goal of this dissertation is to provide further understanding of the specific role played by AVP- and VIP-ergic projections from the SCN to these neuropeptidergic cell phenotypes in LH surge generation. In Chapter 2, a Cre recombinase-dependent, viral tract tracer was used to examine SCN VIP- and AVP-ergic projections to RFRP-3 and kisspeptin cell populations in VIP-Cre and AVP-Cre mouse driver lines, respectively. In Chapters 3 and 4, chemogenetic manipulation was used to determine the specific functional role of these VIP- and AVP-expressing SCN cells in stimulation of the reproductive axis and initiation of the LH surge. More specifically, VIP and AVP neurons were stimulated in the morning, prior to the LH surge, or inhibited in the afternoon around the time of the LH surge using AAV-hM3Dq and hM4Di, respectively. Brains were collected and analyzed for GnRH, kisspeptin, and RFRP-3 cellular activity using double-label immunofluorescence. These studies inform our understanding of the complex neural and endocrine networks regulating the physiological processes underlying female reproductive health.