KNDy Neurons of the Hypothalamus and Their Role in GnRH Pulse Generation: an Update

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2024 Jan 3

PMID 38170643

Authors

Aleisha M Moore

Alyssa G Novak

Michael N Lehman

Affiliations

Soon will be listed here.

Abstract

There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) is crucial for the generation of gonadotrophin-releasing hormone (GnRH) pulses in mammals. The initial "KNDy hypothesis" proposed that pulsatile GnRH secretion is elicited by episodic kisspeptin release from KNDy cells following synchronized activation and termination of the population by NKB and dynorphin, respectively. Since then, the role of KNDy cells as a critical component of the pulse generator has been further supported by studies at the single-cell level, demonstrating that the population is both necessary and sufficient for pulsatility. In addition, there have been considerable modifications and expansion of the original hypothesis, including work demonstrating the critical role of glutamate in synchronization of the KNDy cell network, functional interactions with other ARC subpopulations, and the existence of species differences in the role of dynorphin in pulse generation. Here we review these recent changes and discuss how the translation of these findings has led to the development of new therapies for disorders related to pulse generation. We also outline critical gaps in knowledge that are currently limiting the application of KNDy research in the clinic, particularly regarding the role of dynorphin in pulse generation in primates.

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References

Belchetz P, Plant T, Nakai Y, Keogh E, Knobil E . Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978; 202(4368):631-3. DOI: 10.1126/science.100883. View

Moore A, Coolen L, Porter D, Goodman R, Lehman M . KNDy Cells Revisited. Endocrinology. 2018; 159(9):3219-3234. PMC: 6098225. DOI: 10.1210/en.2018-00389. View

Herde M, Iremonger K, Constantin S, Herbison A . GnRH neurons elaborate a long-range projection with shared axonal and dendritic functions. J Neurosci. 2013; 33(31):12689-97. PMC: 6618539. DOI: 10.1523/JNEUROSCI.0579-13.2013. View

Ciofi P, Krause J, Prins G, Mazzuca M . Presence of nuclear androgen receptor-like immunoreactivity in neurokinin B-containing neurons of the hypothalamic arcuate nucleus of the adult male rat. Neurosci Lett. 1994; 182(2):193-6. DOI: 10.1016/0304-3940(94)90795-1. View

Qiu J, Nestor C, Zhang C, Padilla S, Palmiter R, Kelly M . High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. Elife. 2016; 5. PMC: 4995096. DOI: 10.7554/eLife.16246. View

De Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G . A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997; 337(22):1597-602. DOI: 10.1056/NEJM199711273372205. View

Seminara S, Messager S, Chatzidaki E, Thresher R, Acierno Jr J, Shagoury J . The GPR54 gene as a regulator of puberty. N Engl J Med. 2003; 349(17):1614-27. DOI: 10.1056/NEJMoa035322. View

Evans N, Dahl G, Mauger D, Padmanabhan V, Thrun L, Karsch F . Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system. Endocrinology. 1995; 136(12):5511-9. DOI: 10.1210/endo.136.12.7588302. View

de Croft S, Boehm U, Herbison A . Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology. 2013; 154(8):2750-60. DOI: 10.1210/en.2013-1231. View

10.

Ferin M, van Vugt D, Wardlaw S . The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res. 1984; 40:441-85. DOI: 10.1016/b978-0-12-571140-1.50015-3. View

11.

Estrada K, Clay C, Pompolo S, Smith J, Clarke I . Elevated KiSS-1 expression in the arcuate nucleus prior to the cyclic preovulatory gonadotrophin-releasing hormone/lutenising hormone surge in the ewe suggests a stimulatory role for kisspeptin in oestrogen-positive feedback. J Neuroendocrinol. 2006; 18(10):806-9. DOI: 10.1111/j.1365-2826.2006.01485.x. View

12.

Podfigurna A, Maciejewska-Jeske M, Meczekalski B, Genazzani A . Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea. Endocrine. 2020; 70(3):635-643. PMC: 7674559. DOI: 10.1007/s12020-020-02481-4. View

13.

Merkley C, Porter K, Coolen L, Hileman S, Billings H, Drews S . KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology. 2012; 153(11):5406-14. PMC: 3473209. DOI: 10.1210/en.2012-1357. View

14.

McQuillan H, Clarkson J, Kauff A, Han S, Yip S, Cheong I . Definition of the estrogen negative feedback pathway controlling the GnRH pulse generator in female mice. Nat Commun. 2022; 13(1):7433. PMC: 9718805. DOI: 10.1038/s41467-022-35243-z. View

15.

Lehman M, Merkley C, Coolen L, Goodman R . Anatomy of the kisspeptin neural network in mammals. Brain Res. 2010; 1364:90-102. PMC: 2992597. DOI: 10.1016/j.brainres.2010.09.020. View

16.

Goubillon M, Forsdike R, Robinson J, Ciofi P, Caraty A, Herbison A . Identification of neurokinin B-expressing neurons as an highly estrogen-receptive, sexually dimorphic cell group in the ovine arcuate nucleus. Endocrinology. 2000; 141(11):4218-25. DOI: 10.1210/endo.141.11.7743. View

17.

Dubois S, Acosta-Martinez M, DeJoseph M, Wolfe A, Radovick S, Boehm U . Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology. 2014; 156(3):1111-20. PMC: 4330313. DOI: 10.1210/en.2014-1851. View

18.

Voliotis M, Li X, De Burgh R, Lass G, Ivanova D, McIntyre C . Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network. Elife. 2021; 10. PMC: 8651288. DOI: 10.7554/eLife.71252. View

19.

Messager S, Chatzidaki E, Ma D, Hendrick A, Zahn D, Dixon J . Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005; 102(5):1761-6. PMC: 545088. DOI: 10.1073/pnas.0409330102. View

20.

Foradori C, Coolen L, Fitzgerald M, Skinner D, Goodman R, Lehman M . Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus. Endocrinology. 2002; 143(11):4366-74. DOI: 10.1210/en.2002-220586. View