Cited by 150Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyRegulation of Appetite and Obesity

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Regulation of Arcuate Neurons Coexpressing Kisspeptin, Neurokinin B, and Dynorphin by Modulators of Neurokinin 3 and κ-Opioid Receptors in Adult Male Mice

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Ruka, Kristen A., Burger, Laura L., Moenter, Suzanne M.·2013·Endocrinology

DOI 10.1210/en.2013-1268PMC PMC3713217

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Abstract

Pulsatile GnRH release is essential to fertility and is modulated by gonadal steroids, most likely via steroid-sensitive afferents. Arcuate neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are steroid-sensitive and have been postulated to both generate GnRH pulses and mediate steroid feedback on pulse frequency. KNDy neurons are proposed to interact with one another via NKB and dynorphin to activate and inhibit the KNDy network, respectively, and thus alter kisspeptin output to GnRH neurons. To test the roles of NKB and dynorphin on KNDy neurons and the steroid sensitivity of these actions, targeted extracellular recordings were made of Tac2(NKB)-GFP-identified neurons from castrate and intact male mice. Single-cell PCR confirmed most of these cells had a KNDy phenotype. The neurokinin 3 receptor (NK3R) agonist senktide increased action potential firing activity of KNDy neurons. Dynorphin reduced spontaneous KNDy neuron activity, but antagonism of κ-opioid receptors (KOR) failed to induce firing activity in quiescent KNDy neurons. Senktide-induced activation was greater in KNDy neurons from castrate mice, whereas dynorphin-induced suppression was greater in KNDy neurons from intact mice. Interactions of dynorphin with senktide-induced activity were more complex; dynorphin treatment after senktide had no consistent inhibitory effect, whereas pretreatment with dynorphin decreased senktide-induced activity only in KNDy neurons from intact but not castrate mice. These data suggest dynorphin-mediated inhibition of senktide-induced activity requires gonadal steroid feedback. Together, these observations support the hypotheses that activation of NK3R and KOR, respectively, excites and inhibits KNDy neurons and that gonadal steroids modulate these effects.

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Hypothalamic kisspeptin neurons as potential mediators of estradiol negative and positive feedback
Starrett, J. R., & Moenter, S. M. (2023) · Peptides · doi:10.1016/j.peptides.2023.170963 · Cited by 29
KNDy neurones and GnRH / LH pulse generation: Current understanding and future aspects
Uenoyama, Y., & Tsukamura, H. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13285 · Cited by 32
Effects of menopause on temperature regulation
Gombert, M., Vesterdorf, K., Fuller, A., Maloney, S. K., & Baker, F. C. (2025) · Temperature · doi:10.1080/23328940.2025.2484499 · Cited by 45
Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis
Matsui, H., & Asami, T. (2014) · Neuroendocrinology · doi:10.1159/000357809 · Cited by 32
Cellular and molecular mechanisms regulating the KNDy neuronal activities to generate and modulate GnRH pulse in mammals
Ikegami, K., Watanabe, Y., Nakamura, S., Goto, T., Inoue, N., Uenoyama, Y., & Tsukamura, H. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100968 · Cited by 32
Do Substance P and Neurokinin A Play Important Roles in the Control of LH Secretion in Ewes?
Fergani, C., Mazzella, L. K., Coolen, L. M., McCosh, R. B., Hardy, S. L., Newcomb, N., Grachev, P., Lehman, M. N., & Goodman, R. L. (2016) · Endocrinology · doi:10.1210/en.2016-1565 · Cited by 28
Neurokinin B Receptor Antagonism Decreases Luteinising Hormone Pulse Frequency and Amplitude and Delays Puberty Onset in the Female Rat
Li, S. Y., Li, X. F., Hu, M., Shao, B., Poston, L., Lightman, S. L., & O'Byrne, K. T. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12167 · Cited by 28
Electrophysiology of Arcuate Neurokinin B Neurons in Female Tac2-EGFP Transgenic Mice
Cholanian, M., Krajewski, S. J., Levine, R. B., McMullen, N. T., & Rance, N. E. (2014) · Endocrinology · doi:10.1210/en.2014-1065 · Cited by 23
“Notably, a recent study of arcuate Tac2-EGFP neurons showed a reduced excitatory response to senktide (an NK3R agonist) in intact male mice, compared with orchidectomized mice (34).”
BackgroundResultInfluential
Kisspeptin-Gpr54 Signaling at the GnRH Neuron Is Necessary for Negative Feedback Regulation of Luteinizing Hormone Secretion in Female Mice
Yeo, S., Clarkson, J., & Herbison, A. E. (2014) · Neuroendocrinology · doi:10.1159/000368608 · Cited by 25
Colocalization of Cocaine- and Amphetamine-Regulated Transcript with Kisspeptin and Neurokinin B in the Human Infundibular Region
Skrapits, K., Borsay, B. Á., Herczeg, L., Ciofi, P., Bloom, S. R., Ghatei, M. A., Dhillo, W. S., Liposits, Z., & Hrabovszky, E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103977 · Cited by 24
“Such autoreceptors include the NK3 [2,9,10], NK1 [11] and NK2 [11] tachykinin receptors through which NKB can excite [11–13], and the k-opioid autoreceptor through which dynorphin and selective kappa-opioid receptor agonists can inhibit [11,13] KNDy neuronal activity.”
Background
Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates
Terasawa, E., Garcia, J. P., Seminara, S. B., & Keen, K. L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00148 · Cited by 24
“While direct application of the NK3R agonist senktide on sliced brain preparation stimulates GnRH neuronal activity in mice (36) and the NK3R is described in close proximity to GnRH neuroterminals in rats and sheep (37, 38), only a small number or no GnRH neuronal cell bodies express NK3R in rat and mice (37, 39, 40).”
Background
The role of non-neuronal cells in hypogonadotropic hypogonadism
Smedlund, K., & Hill, J. W. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110996 · Cited by 26
“This population acts as a “pulse generator” that stimulates GnRH pulses under the control of negative feedback by male or female sex steroids (Herbison, 1998; Ciofi et al., 1994; Smith et al., 2005; Navarro et al., 2009a; Ruka et al., 2013).”
Background
Impose of KNDy/GnRH neural circuit in PCOS, ageing, cancer and Alzheimer’s disease: StAR actions in prevention of neuroendocrine dysfunction
Panda, S. P., Kesharwani, A., Singh, G. D., Prasanth, D., Vatchavai, B. R., Kumari, P. V. K., Panda, S. K., & Mallick, S. P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102086 · Cited by 24
Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism
Nandankar, N., Negrón, A. L., Wolfe, A., Levine, J. E., & Radovick, S. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00088.2021 · Cited by 24
A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output in male mice
Vanacker, C., DeFazio, R. A., Sykes, C. M., & Moenter, S. M. (2021) · eLife · doi:10.7554/elife.68205 · Cited by 23
Chronic Oestradiol Reduces the Dendritic Spine Density of KND y (Kisspeptin/Neurokinin B/Dynorphin) Neurones in the Arcuate Nucleus of Ovariectomised Tac2‐Enhanced Green Fluorescent Protein Transgenic Mice
Cholanian, M., Krajewski, S. J., McMullen, N. T., & Rance, N. E. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12263 · Cited by 23
17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice
Conde, K., & Roepke, T. A. (2019) · Neuroendocrinology · doi:10.1159/000503146 · Cited by 24
A neurokinin 3 receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle†
Nakamura, S., Wakabayashi, Y., Yamamura, T., Ohkura, S., & Matsuyama, S. (2017) · Biology of Reproduction · doi:10.1093/biolre/iox068 · Cited by 23
Kisspeptin Variations in Patients with Polycystic Ovary Syndrome—A Prospective Case Control Study
Akad, M., Socolov, R. V., Furnică, C., Covali, R. A., Stan, C. D., Crauciuc, E., & Păvăleanu, I. (2022) · Medicina · doi:10.3390/medicina58060776 · Cited by 22
“in 2013 showed that the amount of KISS1 and kisspeptin cells in the arcuate nucleus positively correlates with LH levels in rodent subjects with PCOS [34].”
Background
Kisspeptin neuron electrophysiology: Intrinsic properties, hormonal modulation, and regulation of homeostatic circuits
Jamieson, B. B., & Piet, R. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101006 · Cited by 24
Gonadal steroid neuromodulation of developing and mature hypothalamic neuronal networks
Campbell, R. E., & Herbison, A. E. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.06.003 · Cited by 21
Prenatal Androgen Treatment Does Not Alter the Firing Activity of Hypothalamic Arcuate Kisspeptin Neurons in Female Mice
Gibson, A. G., Jaime, J., Burger, L. L., & Moenter, S. M. (2021) · eNeuro · doi:10.1523/eneuro.0306-21.2021 · Cited by 20
“9 quality check, this test is also biologically relevant as senktide activates firing activity of Tac2224 GFP neurons (Ruka et al., 2013), and it is possible that age and treatment alter this.”
BackgroundMethodResultInfluential
Mechanism of Arcuate Kisspeptin Neuron Synchronization in Acute Brain Slices From Female Mice
Morris, P. G., & Herbison, A. E. (2023) · Endocrinology · doi:10.1210/endocr/bqad167 · Cited by 21
“…glutamate, ARN KISS neurons co-express neurokinin B (NKB) and dynorphin in almost all mammals (8, 9), and experiments in mice have shown that essentially all ARN KISS neurons synthesize functional tachykinin and kappa opioid receptors that activate and suppress their firing, respectively (10, 11 ).”
Background
The human hypothalamic kisspeptin system: Functional neuroanatomy and clinical perspectives
Hrabovszky, E., Takács, S., Rumpler, É., & Skrapits, K. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820107-7.00017-3 · Cited by 19
The 3rd World Conference on Kisspeptin, “Kisspeptin 2017: Brain and Beyond”: Unresolved questions, challenges and future directions for the field
Lehman, M. N., Coolen, L. M., Steiner, R. A., Neal-Perry, G. S., Wang, L., Moenter, S. M., Moore, A. M., Goodman, R. L., Yeo, S. ‐., Padilla, S. L., et al. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12600 · Cited by 17
A CRH Receptor Type 1 Agonist Increases GABA Transmission to GnRH Neurons in a Circulating-Estradiol-Dependent Manner
Phumsatitpong, C., Guzman, R. M. D., Zuloaga, D. G., & Moenter, S. M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa140 · Cited by 18
Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents
DeFazio, R. A., Navarro, M. A., Adams, C. E., Milescu, L. S., & Moenter, S. M. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0378-19.2019 · Cited by 17
“Arcuate kisspeptin neurons were visualized in brain slices from Tac2-enhanced green fluorescent protein (GFP) BAC transgenic mice [015495-UCD/ STOCK Tg (Tac2-EGFP)381Gsat, Mouse Mutant Regional Resource Center; Ruka et al., 2013] and kisspeptin-hrGFP transgenic mice (Cravo et al., 2013).”
BackgroundMethod
Heterogeneity in GnRH and kisspeptin neurons and their significance in vertebrate reproductive biology
Ogawa, S., & Parhar, I. S. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100963 · Cited by 15
Quercetin-loaded PEGylated liposomes alleviate testicular dysfunction in alloxan-induced diabetic rats: The role of Kisspeptin/Neurokinin B/Dynorphin pathway
Mansour, M. F., Behairy, A., Mostafa, M., Khamis, T., Alsemeh, A. E., Ahmed, N. M. Q., & El-Emam, M. M. A. (2025) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2025.117337 · Cited by 14
Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice
de Miera, C. S., Bellefontaine, N., Allen, S. J., Myers, M. G., & Elias, C. F. (2024) · eLife · doi:10.7554/elife.93204 · Cited by 16
“These findings indicate that blockade of glutamatergic neurotransmission in LepRb neurons disrupts key components of the GnRH pulse generator ( Han et al., 2023 ; Ruka et al., 2013 ; Uenoyama and Tsukamura, 2023 ), leading ultimately to reproductive deficits.”
Background
Conditional Deletion of KOR (Oprk1) in Kisspeptin Cells Does Not Alter LH Pulses, Puberty, or Fertility in Mice
Coutinho, E. A., Esparza, L. A., Hudson, A. D., Rizo, N., Steffen, P., & Kauffman, A. S. (2022) · Endocrinology · doi:10.1210/endocr/bqac175 · Cited by 14
Growth variations with opposite clinical outcomes and the emerging role of IGF-1
Papadimitriou, A., Marakaki, C., & Papadimitriou, D. T. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.02.004 · Cited by 14
Social isolation and aggression training lead to escalated aggression and hypothalamus-pituitary-gonad axis hyperfunction in mice
Oliveira, V. E. D. M., Evrard, F., Faure, M., & Bakker, J. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01808-3 · Cited by 14
Importance of neuroanatomical data from domestic animals to the development and testing of the KNDy hypothesis for GnRH pulse generation
Lehman, M. N., Coolen, L. M., & Goodman, R. L. (2020) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2020.106441 · Cited by 13
Development and Modulation of Female Reproductive Function by Circadian Signals
Gotlieb, N., Moeller, J., & Kriegsfeld, L. J. (2020) · Masterclass in neuroendocrinology · doi:10.1007/978-3-030-40002-6_16 · Cited by 14
“In contrast to NKB, dynorphin inhibits Arc kisspeptin secretion and is thought to participate in the termination of each pulse (Goodman et al. 2013; Ruka et al. 2013).”
Background
Tachykinin signaling defines distinct populations of glia in the enteric nervous system
Muppirala, A. N., Mitchell, P. E., Courtney, E., Debnath, S., D’Alessandro, L. R., Mani, N., Dadabhoy, M., Robinson, A. F., Díaz-Muñoz, C., Paraskevopoulou, M. D., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.11.030 · Cited by 11
“39 In the intestine, Tacr3 was expressed in the MP in juveniles (3 weeks) and adults (8–12 weeks), exclusively within tdTomato + cells (Figure S2D).”
Kisspeptin in functional hypothalamic amenorrhea: Pathophysiology and therapeutic potential
Patel, A., Koysombat, K., Pierret, A. C. S., Young, M., Comninos, A. N., Dhillo, W. S., & Abbara, A. (2024) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15220 · Cited by 17
Investigation of irisin's role in pubertal onset physiology in female rats
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The Roles of Neurokinins and Endogenous Opioid Peptides in Control of Pulsatile LH Secretion
Weems, P. W., Lehman, M. N., Coolen, L. M., & Goodman, R. L. (2018) · Vitamins and hormones · doi:10.1016/bs.vh.2018.01.011 · Cited by 11
GnRH Neurons on LSD: A Year of Rejecting Hypotheses That May Have Made Karl Popper Proud
Moenter, S. M. (2017) · Endocrinology · doi:10.1210/en.2017-03040 · Cited by 11
“Treatment of brain slices from intact mice with the KOR antagonist norbinaltorphimine had no effect on long-term firing pattern, consistent with observation of its lack of effect on shortterm firing rate (22).”
Background
Estrogen promotes gonadotropin-releasing hormone expression by regulating tachykinin 3 and prodynorphin systems in chicken
Wu, X., Zhang, Z., Li, Y., Zhao, Y., Ren, Y., Tian, Y., Hou, M., Guo, Y., Li, Q., Tian, W., et al. (2024) · Poultry Science · doi:10.1016/j.psj.2024.103820 · Cited by 10

Authors: Ruka, K. A., Burger, L. L., & Moenter, S. M.
Affiliations: University of Michigan (US)
Corresponding author: Moenter, Suzanne M.
ORCID: Burger, Laura L.
Moenter, Suzanne M.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2013-08-01
Volume: 154
Issue: 8
Pages: 2761-2771
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2013-1268
PMC: PMC3713217
OpenAlex: W2001560124
Cited by: 150
References: 72
Citations by year: 2026: 5 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 8 · 2019: 12 · 2018: 13 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 21 · 2013: 5
FWCI: 17.37
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Endocrinology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD34860, R01HD034860)
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 › Regulation of Appetite and Obesity
Keywords: kisspeptin, neurokinin B, dynorphin, KNDy neurons, arcuate nucleus, neurokinin-3 receptor, kappa opioid receptor, senktide, gonadal steroid feedback, pulsatile GnRH release, neuronal firing, castration
MeSH terms: Animals, Arcuate Nucleus of Hypothalamus, Dynorphins, Gonadotropin-Releasing Hormone, Male, Membrane Potentials, Mice, Transgenic, Neurons, Orchiectomy, Peptide Fragments, Pyrrolidines, Substance P, Time Factors, Neurokinin B, Receptors, Opioid, kappa, Receptors, Neurokinin-3, Benzeneacetamides, Green Fluorescent Proteins, Mice, Kisspeptins

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Regulation of Arcuate Neurons Coexpressing Kisspeptin, Neurokinin B, and Dynorphin by Modulators of Neurokinin 3 and κ-Opioid Receptors in Adult Male Mice

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