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Cited by 599Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyNeuroendocrine regulation and behavior

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Neurokinin B and Dynorphin A in Kisspeptin Neurons of the Arcuate Nucleus Participate in Generation of Periodic Oscillation of Neural Activity Driving Pulsatile Gonadotropin-Releasing Hormone Secretion in the Goat

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Wakabayashi, Yoshihiro, Nakada, Tomoaki, Murata, Ken, Ohkura, Satoshi, Mogi, Kazutaka, Navarro, Victor M., Clifton, Donald K., Mori, Yuji, Tsukamura, Hiroko, Maeda, Kei-Ichiro, Steiner, Robert A., Okamura, Hiroaki·2010·The Journal of Neuroscience
DOI 10.1523/jneurosci.5848-09.2010PMC PMC6633939
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Abstract

Gonadotropin-releasing hormone (GnRH) neurons in the basal forebrain are the final common pathway through which the brain regulates reproduction. GnRH secretion occurs in a pulsatile manner, and indirect evidence suggests the kisspeptin neurons in the arcuate nucleus (ARC) serve as the central pacemaker that drives pulsatile GnRH secretion. The purpose of this study was to investigate the possible coexpression of kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn) in neurons of the ARC of the goat and evaluate their potential roles in generating GnRH pulses. Using double and triple labeling, we confirmed that all three neuropeptides are coexpressed in the same population of neurons. Using electrophysiological techniques to record multiple-unit activity (MUA) in the medial basal hypothalamus, we found that bursts of MUA occurred at regular intervals in ovariectomized animals and that these repetitive bursts (volleys) were invariably associated with discrete pulses of luteinizing hormone (LH) (and by inference GnRH). Moreover, the frequency of MUA volleys was reduced by gonadal steroids, suggesting that the volleys reflect the rhythmic discharge of steroid-sensitive neurons that regulate GnRH secretion. Finally, we observed that central administration of Dyn-inhibit MUA volleys and pulsatile LH secretion, whereas NKB induced MUA volleys. These observations are consistent with the hypothesis that kisspeptin neurons in the ARC drive pulsatile GnRH and LH secretion, and suggest that NKB and Dyn expressed in those neurons are involved in the process of generating the rhythmic discharge of kisspeptin.

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Figure 1 Colocalization of kisspeptin, NKB, and Dyn in the caudal ARC and ME of the goat. Photomicrographs of sections of the ARC stained by immunocytochemistry for kisspeptin ( A ) and NKB ( B ), or kisspeptin ( D ) and Dyn ( E ), are shown. C and F are computer-aid merged images of A and B , or D and E , respectively. An arrow in A or C indicates a cell body containing immunoreactivity (ir) for kisspeptin but not NKB-ir. The large arrows in D or F , or small arrows in E or F , show some cell bodies containing exclusively kisspeptin-ir or Dyn-ir, respectively. Note that numerous kisspeptin/NKB- or kisspeptin/Dyn-positive fibers surround immunopositivecellbodies. G and H are mergedimagesofsectionsoftheMEdoublestainedforkisspeptin/NKBorkisspeptin/Dyn, respectively. The arrowhead in G indicates a fiber with only NKB-ir. The arrowheads in H show fibers with exclusively Dyn-ir. I-K show kisspeptin-ir and positive signals for NKB and PDYN in triple-label histochemistry, respectively. L is a merged image of I-K . MEe, External layer of median eminence; pt, pars tuberalis. Scale bars: A-C , I-L , 50 𝛍 m; D-F , 100 𝛍 m; G , H , 25 𝛍 m.
Figure 1 Colocalization of kisspeptin, NKB, and Dyn in the caudal ARC and ME of the goat. Photomicrographs of sections of the ARC stained by immunocytochemistry for kisspeptin ( A ) and NKB ( B ), or kisspeptin ( D ) and Dyn ( E ), are shown. C and F are computer-aid merged images of A and B , or D and E , respectively. An arrow in A or C indicates a cell body containing immunoreactivity (ir) for kisspeptin but not NKB-ir. The large arrows in D or F , or small arrows in E or F , show some cell bodies containing exclusively kisspeptin-ir or Dyn-ir, respectively. Note that numerous kisspeptin/NKB- or kisspeptin/Dyn-positive fibers surround immunopositivecellbodies. G and H are mergedimagesofsectionsoftheMEdoublestainedforkisspeptin/NKBorkisspeptin/Dyn, respectively. The arrowhead in G indicates a fiber with only NKB-ir. The arrowheads in H show fibers with exclusively Dyn-ir. I-K show kisspeptin-ir and positive signals for NKB and PDYN in triple-label histochemistry, respectively. L is a merged image of I-K . MEe, External layer of median eminence; pt, pars tuberalis. Scale bars: A-C , I-L , 50 𝛍 m; D-F , 100 𝛍 m; G , H , 25 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 2 Photomicrographs showing the placement of MUA recording electrodes in three goats [no. Y69 ( A ), no. 709 ( B ), and no. 713 ( C )] from which MUA was successfully recorded. Sections were immunostained for kisspeptin. A pair of brackets indicates the area where a trace of a bundle of electrodes is observed, and a magnification of the indicated area is shown on the right side of each panel. Some kisspeptin-immunopositive cell bodies are shown by arrowheads. Note that because it was not possible to perfuse goats Y69 and 709, immunostaining of their sections was poor. 3V, Third ventricle. Scale bars: left panels, 500 𝛍 m; right panels, 100 𝛍 m.
Figure 2 Photomicrographs showing the placement of MUA recording electrodes in three goats [no. Y69 ( A ), no. 709 ( B ), and no. 713 ( C )] from which MUA was successfully recorded. Sections were immunostained for kisspeptin. A pair of brackets indicates the area where a trace of a bundle of electrodes is observed, and a magnification of the indicated area is shown on the right side of each panel. Some kisspeptin-immunopositive cell bodies are shown by arrowheads. Note that because it was not possible to perfuse goats Y69 and 709, immunostaining of their sections was poor. 3V, Third ventricle. Scale bars: left panels, 500 𝛍 m; right panels, 100 𝛍 m.CC-BY-NC-SA · From the PDF
Figure3 Effect of NKB on the MUA andplasmaLHintheOVXgoat.Representativeprofilesofthe MUAandplasmaLHconcentrationsinOVXanimalsthatreceivedanintracerebroventricularinjection of vehicle ( A ) or 0.2 ( B ) or 2 nmol ( C ) of NKB are shown. The arrow indicates timing of injection.
Figure3 Effect of NKB on the MUA andplasmaLHintheOVXgoat.Representativeprofilesofthe MUAandplasmaLHconcentrationsinOVXanimalsthatreceivedanintracerebroventricularinjection of vehicle ( A ) or 0.2 ( B ) or 2 nmol ( C ) of NKB are shown. The arrow indicates timing of injection.CC-BY-NC-SA · From the PDF
Image 4
CC-BY-NC-SA · From the PDF
Figure 5 Effects of Dyn and nor-BNI on the MUA and plasma LH in the OVX goat. A , Representative profiles of MUA and plasma LHconcentrations in one animal that received an intracerebroventricular injection of 2 nmol of Dyn are shown. The arrow indicates timing of injection. B , Representative profiles of MUA and plasma LH concentrations in one animal that received an intracerebroventricular infusion of nor-BNI at a rate of 60 nmol H18528 600 𝛍 l -1 H18528 h -1 for 2 h are shown. The bar indicates the period of infusion.
Figure 5 Effects of Dyn and nor-BNI on the MUA and plasma LH in the OVX goat. A , Representative profiles of MUA and plasma LHconcentrations in one animal that received an intracerebroventricular injection of 2 nmol of Dyn are shown. The arrow indicates timing of injection. B , Representative profiles of MUA and plasma LH concentrations in one animal that received an intracerebroventricular infusion of nor-BNI at a rate of 60 nmol H18528 600 𝛍 l -1 H18528 h -1 for 2 h are shown. The bar indicates the period of infusion.CC-BY-NC-SA · From the PDF
Figure 6 Schematic representation of the role of ARC kisspeptin/NKB/Dyn neurons in the generation of the pulsatile GnRH release. According to this model, kisspeptin/NKB/Dyn neurons in the ARC form a neural circuit by their collaterals and dendrites. Within the neural circuit, NKB/NK3 signaling plays the role of accelerator, whereas Dyn/KOR signaling serves as a brake on activation of kisspeptin/NKB/Dyn neurons. Through the reciprocal actions of NKB/NK3 and Dyn/KOR signaling, rhythmic oscillation of neural activity is generated in kisspeptin/NKB/Dyn neurons, which in turn induces pulsatile kisspeptin release at the ME and hence pulsatile GnRH release into the portal circulation. Thus, ARC kisspeptin/NKB/Dyn neurons would act as the GnRH pulse generator through the coordinated interaction between three peptides. See text for details.
Figure 6 Schematic representation of the role of ARC kisspeptin/NKB/Dyn neurons in the generation of the pulsatile GnRH release. According to this model, kisspeptin/NKB/Dyn neurons in the ARC form a neural circuit by their collaterals and dendrites. Within the neural circuit, NKB/NK3 signaling plays the role of accelerator, whereas Dyn/KOR signaling serves as a brake on activation of kisspeptin/NKB/Dyn neurons. Through the reciprocal actions of NKB/NK3 and Dyn/KOR signaling, rhythmic oscillation of neural activity is generated in kisspeptin/NKB/Dyn neurons, which in turn induces pulsatile kisspeptin release at the ME and hence pulsatile GnRH release into the portal circulation. Thus, ARC kisspeptin/NKB/Dyn neurons would act as the GnRH pulse generator through the coordinated interaction between three peptides. See text for details.CC-BY-NC-SA · From the PDF

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Metadata

Authors
Wakabayashi, Y., Nakada, T., Murata, K., Ohkura, S., Mogi, K., Navarro, V. M., Clifton, D. K., Mori, Y., Tsukamura, H., Maeda, K.-I., Steiner, R. A., & Okamura, H.
Affiliations
  • Institute of Agrobiological Sciences (JP)
  • Nagoya University (JP)
  • University of Washington (US)
  • The University of Tokyo (JP)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2010-02-24
Volume
30
Issue
8
Pages
3124-3132
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.5848-09.2010
PMC
PMC6633939
OpenAlex
W2045555035
Cited by
597
References
42
Citations by year
2026: 12 · 2025: 27 · 2024: 19 · 2023: 24 · 2022: 32 · 2021: 36 · 2020: 38 · 2019: 36 · 2018: 42 · 2017: 39 · 2016: 42 · 2015: 42 · 2014: 54 · 2013: 48 · 2012: 47
FWCI
58.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5u54hd012629-31)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD049651, U54-HD-12629, U54HD-012629)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
Keywords
kisspeptin neurons, arcuate nucleus, neurokinin B, dynorphin A, pulsatile GnRH secretion, luteinizing hormone, multi-unit activity, goats, neuroendocrine regulation of reproduction
MeSH terms
Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Biological Clocks, Dynorphins, Electrophysiology, Female, Goats, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Neurons, Neurosecretory Systems, Ovariectomy, Periodicity, Proteins, Reproduction, Gonadal Steroid Hormones, Neurokinin B, Tumor Suppressor Proteins, Estrous Cycle, Kisspeptins

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