title: Circadian Control of the Female Reproductive Axis Through Gated Responsiveness of the RFRP-3 System to VIP Signaling.
abstract: Throughout most of the ovulatory cycle, estrogen negative feedback restrains the GnRH neuronal system. Just before ovulation, however, estrogen negative feedback is removed to permit stimulation of the preovulatory GnRH/LH surge (positive feedback) by the circadian clock in the suprachiasmatic nucleus (SCN). The mammalian ortholog of avian gonadotropin-inhibitory hormone, RFamide-related peptide 3 (RFRP-3), participates in the circadian-timed removal of estrogen negative feedback to permit the LH surge. The present study examined the specific neurochemical means by which the SCN controls RFRP-3 activity and explored whether the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to precisely time the LH surge. We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from SCN-derived vasopressin-ergic and vasoactive intestinal peptide (VIP)-ergic terminal fibers. Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas vasopressin was without effect at either time point. Double-label in situ hybridization for Rfrp-3 and the VIP receptors VPAC1 and VPAC2 revealed that the majority of RFRP-3 cells do not coexpress either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly. The timing of this VIP-mediated disinhibition is further coordinated via temporally gated responsiveness of RFRP-3 cells to circadian signaling. Together, these findings reveal a novel circadian hierarchy of control coordinating the preovulatory LH surge and ovulation.
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Kimberly A
authors: KA
authors: Russo
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Janet L
authors: JL
authors: La
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Shannon B Z
authors: SB
authors: Stephens
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Matthew C
authors: MC
authors: Poling
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Namita A
authors: NA
authors: Padgaonkar
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Kimberly J
authors: KJ
authors: Jennings
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: David J
authors: DJ
authors: Piekarski
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Alexander S
authors: AS
authors: Kauffman
authors: Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, Berkeley, California 94720; and Department of Reproductive Medicine (S.B.Z.S., M.C.P., A.S.K.), University of California, San Diego, La Jolla, California 92093.
authors: Lance J
authors: LJ
authors: Kriegsfeld
mesh_terms: D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D006224:Cricetinae; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D008647:Mesocricetus; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010060:Ovulation / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*; D014667:Vasopressins / Q000378:metabolism
chemical_list: D009479:Neuropeptides; C416987:RFamide peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014667:Vasopressins; D007987:Gonadotropin-Releasing Hormone; D014660:Vasoactive Intestinal Peptide; D007986:Luteinizing Hormone