The Journal of Neuroscience, September 23, 2009, 29(38):11859-11866; doi:10.1523/JNEUROSCI.1569-09.2009
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Behavioral/Systems/Cognitive
Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse
Victor M. Navarro,1
Michelle L. Gottsch,2
Charles Chavkin,3
Hiroaki Okamura,4
Donald K. Clifton,2 and
Robert A. Steiner1,2
Departments of 1Physiology and Biophysics, 2Obstetrics and Gynecology, and 3Pharmacology, University of Washington, Seattle, Washington 98195, and 4Laboratory of Neurobiology, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki 305-0901, Japan
Correspondence should be addressed to Robert A. Steiner, University of Washington, Department of Physiology and Biophysics, Box 357290, Seattle, WA 98195-7290. Email: steiner{at}u.washington.edu
Kisspeptin is encoded by the Kiss1 gene, and kisspeptin signaling plays a critical role in reproduction. In rodents, kisspeptin neurons in the arcuate nucleus (Arc) provide tonic drive to gonadotropin-releasing hormone (GnRH) neurons, which in turn supports basal luteinizing hormone (LH) secretion. Our objectives were to determine whether preprodynorphin (Dyn) and neurokinin B (NKB) are coexpressed in Kiss1 neurons in the mouse and to evaluate its physiological significance. Using in situ hybridization, we found that Kiss1 neurons in the Arc of female mice not only express the Dyn and NKB genes but also the NKB receptor gene (NK3) and the Dyn receptor [the
opioid receptor (KOR)] gene. We also found that expression of the Dyn, NKB, KOR, and NK3 in the Arc are inhibited by estradiol, as has been established for Kiss1, and confirmed that Dyn and NKB inhibit LH secretion. Moreover, using Dyn and KOR knock-out mice, we found that long-term disruption of Dyn/KOR signaling compromises the rise of LH after ovariectomy. We propose a model whereby NKB and dynorphin act autosynaptically on kisspeptin neurons in the Arc to synchronize and shape the pulsatile secretion of kisspeptin and drive the release of GnRH from fibers in the median eminence.
Received April 1, 2009;
revised June 6, 2009;
accepted July 30, 2009.
Correspondence should be addressed to Robert A. Steiner, University of Washington, Department of Physiology and Biophysics, Box 357290, Seattle, WA 98195-7290. Email: steiner{at}u.washington.edu