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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
Open accessAbstract
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 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.](/paper-figures/d498842463fd4e30a0da05266f332880/neurokinin-b-and-dynorphin-a-in-kisspeptin-neurons-of-the-arcuate-nucleus-figure-2.png)




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In the citing paper
“administration of NKB or Dyn modulates MUA volley frequency in the ovariectomized goat (Wakabayashi et al., 2010)”
From The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach (2019) · cites this paper as Wakabayashi et al., 2010
In the citing paper
“Emerging evidence that KNDy neurons are an important part of the GnRH pulse generator (Lehman et al., 2010; Rance et al., 2010; Wakabayashi et al., 2010) strongly supports the hypothesis that they could also be involved in the generation of flushes.”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Wakabayashi et al., 2010
In the citing paper
“Emerging evidence that KNDy neurons are an important part of the GnRH pulse generator (Lehman et al., 2010; Rance et al., 2010; Wakabayashi et al., 2010) strongly supports the hypothesis that they could also be involved in the generation of flushes.”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Wakabayashi et al., 2010
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Citations
Cites
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“The pulsatile release of gonadotropin-releasing hormone (GnRH) is a prerequisite for sustaining normal gonadotropin secretion in mammals (Knobil, 1980; Karsch, 1984); however, the cellular and molecular mechanisms that generate the rhythmic discharge of GnRH are unknown.”
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“Finally, kisspeptin/ NKB/Dyn neurons in the ARC have been proposed to be a primary site of negative feedback action of E2 and P (Smith et al., 2005a,b, 2007; Burke et al., 2006; Foradori et al., 2006; Goodman et al., 2007), and we demonstrated here that E2 and P suppress the occurrence of MUA…”
BackgroundSelf-citationHan, S.-K., Gottsch, M. L., Lee, K. J., Popa, S. M., Smith, J. T., Jakawich, S. K., Clifton, D. K., Steiner, R. A., & Herbison, A. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3328-05.2005 · Cited by 1,036 · cited 2×
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“Indeed, Topaloglu et al. (2009) have recently shown that mutations of either Trc3 or Tacr3, which encode NKB and NK3, respectively, produce gonadotropin deficiency and pubertal failure in humans.”
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“Kisspeptin neurons in the hypothalamus play a key role in the regulation of GnRH neurons (Oakley et al., 2009), but the precise nature of the interaction between kisspeptin and GnRH neurons is just emerging.”
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“Finally, we tested the hypothesis that NKB and Dyn play crucial roles in driving GnRH pulse generator activity by analyzing the effects of centrally administered NKB, Dyn, and a KOR antagonist on pulsatile MUA and LH secretion.”
BackgroundResultInfluential
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Items 501–599 of 599
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“The ARH was also proposed to be the center of the GnRH “pulse generator” based on in vivo recordings of multi-unit activity [59-62].”
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BackgroundSuetomi, Y., Matsuda, F., Uenoyama, Y., Maeda, K., Tsukamura, H., & Ohkura, S. (2013) · Journal of Reproduction and Development · doi:10.1262/jrd.2013-037 · Cited by 1
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Kisspeptin / metastin ― a novel neuropeptide controlling reproduction
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The Role of Dynorphin in the Onset of Puberty in Female Lambs
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“Dyn has been generally recognized to mediate progesterone negative feedback on GnRH release (Foradori et al., 2005; Goodman et al., 2004; Wakabayashi et al., 2010).”
BackgroundFatores que alteram a ingestão alimentar modulam a atividade de neurônios kisspeptinérgicos?
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“…gene) are thought to synchronize KNDy neuronal activity via neurokinin 3 receptor (NK3R, known as a neurokinin B receptor) and κ-opioid receptor (KOR, known as a dynorphin A receptor) in an autocrine/ paracrine manner in various mammals, such as goats [13], ewes [14], rats [15], and mice [16, 17].”
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“This feature of kisspeptin exclusively found in the ARC has initially been discovered in higher primates and other species including male and female mouse (Keen et al., 2008, Wakabayashi et al., 2010, Navarro et al., 2011).”
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“Ainsi, les neurones KNDy agiraient comme générateur d'impulsions du GnRH. D’après (Wakabayashi et al., 2010).”
InfluentialIMPACT DE L’HYPERCORTICISME SUR L’AXE GONADOTROPE FEMELLE
Ayrout, M. (2018) · theses.fr (ABES) · doi:10.70675/194a6ff5z99f6z4ef0z800ez5473528e7a30
Characterization of tachykinin system and role in reproduction in the European eel
Campo, A. (2018) · theses.fr (ABES) · doi:10.70675/d6441c0cz240dz4d84zbcacz1aa6e622f56b
Topaloglu, A. K., Plummer, L., Su, C., Kotan, L. D., Çelmeli, G., Şimşek, E., Zhao, Y., Stamou, M. I., Ahmet, A. N. I. K., Döğer, E., et al. (2026) · medRxiv · doi:10.64898/2026.04.10.26349358
Lages, V. L., Godinho, L. F., Guieiro, A. S., Trindade, T., Costa, B. O., Costa, J. M. M., Pereira, R. R. D. S., Magalhães, C. O. D. E., & Sampaio, K. H. (2026) · Drugs and Drug Candidates · doi:10.3390/ddc5020026
“It has been demonstrated that estradiol exerts inhibitory feedback on a specific population of neurons in the arcuate nucleus, the KNDy neurons [31,32].”
Röblitz, S. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0211
Hypothermic Conditions Impair GnRH Pulse Generator Activity and GametogenesisPreprint
Hagihara, M., Suzuki, D., Hara, J., Abe, T., Sakurai, T., Miyamichi, K., & Goto, T. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.27.747452
“Previous studies have established electrophysiological recordings of multiunit activity from putative ARC kiss neurons in goats ( 16 , 17 ) as well as cell-type-specific chronic Ca 2+ imaging of ARC kiss neural activity in freely moving mice using fiber photometry ( 18 , 19 ).”
eSilva, L. O., West, S. M., Garza, V., Sustaita-Monroe, J. F., King, L., Sellers, H., Weynand, M., Feist, H., Perry, G. A., Sartori, R., et al. (2026) · Biology of Reproduction · doi:10.1093/biolre/ioag198 · Cited by 1
Bizerea, T. O., Chisavu, F., Chisavu, L. A., Pitulice, L., Moga, T. V., Bugi, M.-A., Foghiș, C. F., Isac, R., Mărginean, O., & Balica, N. C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188159 · Cited by 1
Tumurbaatar, T., Oride, A., Cairang, Z., Okada, H., & Kanasaki, H. (2026) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2026.102834
“Numerous studies have shown that hypothalamus kisspeptin neurons are generally located in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) regions [3,4].”
BindingDB (2017) · UC San Diego · doi:10.7270/q2rr216w
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
- 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
- hybrid
- doi.org
- 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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