title: Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals.
abstract: Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-alpha and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.
authors.affiliation: Department of Psychology and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA. kriegsfeld@berkeley.edu
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Kriegsfeld
authors.forename: Dan Feng
authors.initials: DF
authors.lastname: Mei
authors.forename: George E
authors.initials: GE
authors.lastname: Bentley
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ubuka
authors.forename: Alex O
authors.initials: AO
authors.lastname: Mason
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ukena
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
authors.forename: Rae
authors.initials: R
authors.lastname: Silver
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D006224:Cricetinae; D005260:Female; D015870:Gene Expression; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D006062:Gonadotropins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007028:Hypothalamic Hormones / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D009479:Neuropeptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics
chemical_list: D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D007028:Hypothalamic Hormones; D009479:Neuropeptides; D010455:Peptides; C416987:RFamide peptide; D012333:RNA, Messenger; D011987:Receptors, Steroid; D007986:Luteinizing Hormone