The neurobiological mechanism underlying hypothalamic GnRH pulse generation: the role of kisspeptin neurons in the arcuate nucleus.

Published on Jun 28, 2019in F1000Research
· DOI :10.12688/F1000RESEARCH.18356.2
Tony M. Plant65
Estimated H-index: 65
(University of Pittsburgh)
Sources
Abstract
This review recounts the origins and development of the concept of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator. It starts in the late 1960s when striking rhythmic episodes of luteinizing hormone secretion, as reflected by circulating concentrations of this gonadotropin, were first observed in monkeys and ends in the present day. It is currently an exciting time witnessing the application, primarily to the mouse, of contemporary neurobiological approaches to delineate the mechanisms whereby Kiss1/NKB/Dyn (KNDy) neurons in the arcuate nucleus of the hypothalamus generate and time the pulsatile output of kisspeptin from their terminals in the median eminence that in turn dictates intermittent GnRH release and entry of this decapeptide into the primary plexus of the hypophysial portal circulation. The review concludes with an examination of questions that remain to be addressed.
📖 Papers frequently viewed together
2014
8 Citations
20167.08eLife
7 Authors (Jian Qiu, ..., Oline K. Rønnekleiv)
96 Citations
1 Citations
References122
Newest
#1Ei Terasawa (UW: University of Wisconsin-Madison)H-Index: 59
Abstract The pulsatility of GnRH release is essential for reproductive function. The key events in reproductive function, such as puberty onset and ovulatory cycles, are regulated by the frequency and amplitude modulation of pulsatile GnRH release. Abnormal patterns of GnRH pulsatility are seen in association with disease states, such as polycystic ovarian syndrome and anorexia nervosa. Recent studies with physiological, track-tracing, optogenetic and electrophysiological recording experiments i...
6 CitationsSource
#1Su Young Han (University of Otago)H-Index: 8
#2Grace Kane (University of Otago)H-Index: 3
Last. Allan E. Herbison (University of Otago)H-Index: 88
view all 4 authors...
: Kisspeptin neurons located in the hypothalamic arcuate nucleus are thought to represent the GnRH pulse generator responsible for driving pulsatile LH secretion. The recent development of GCaMP6 fiber photometry technology has made it possible to perform long-term recordings of the population activity of the arcuate nucleus kisspeptin (ARNKISS) neurons in conscious-behaving mice. Using this approach, we show that ARNKISS neurons in intact male mice exhibit episodes of synchronized activity that...
24 CitationsSource
#1Allan E. Herbison (University of Otago)H-Index: 88
: The pulsatile release of GnRH and LH secretion is essential for fertility in all mammals. Pulses of LH occur approximately every hour in follicular-phase females and every 2 to 3 hours in luteal-phase females and males. Many studies over the last 50 years have sought to identify the nature and mechanism of the "GnRH pulse generator" responsible for pulsatile LH release. This review examines the characteristics of pulsatile hormone release and summarizes investigations that have led to our pres...
69 CitationsSource
#1Aleisha M. Moore (UMMC: University of Mississippi Medical Center)H-Index: 9
#2Lique M. Coolen (UMMC: University of Mississippi Medical Center)H-Index: 53
Last. Michael N. Lehman (UMMC: University of Mississippi Medical Center)H-Index: 1
view all 5 authors...
: In the past decade since kisspeptin/neurokinin B/dynorphin (KNDy) cells were first identified in the mammalian hypothalamus, a plethora of new research has emerged adding insights into the role of this neuronal population in reproductive neuroendocrine function, including the basis for GnRH pulse generation and the mechanisms underlying the steroid feedback control of GnRH secretion. In this mini-review, we provide an update of evidence regarding the roles of KNDy peptides and their postsynapt...
72 CitationsSource
#1Peyton W. Weems (UMMC: University of Mississippi Medical Center)H-Index: 6
#2Lique M. Coolen (UMMC: University of Mississippi Medical Center)H-Index: 53
Last. Michael N. Lehman (UMMC: University of Mississippi Medical Center)H-Index: 1
view all 7 authors...
A subpopulation of neurons located within the arcuate nucleus, colocalizing kisspeptin, neurokinin B, and dynorphin (Dyn; termed KNDy neurons), represents key mediators of pulsatile GnRH secretion. The KNDy model of GnRH pulse generation proposes that Dyn terminates each pulse. However, it is unknown where and when during a pulse that Dyn is released to inhibit GnRH secretion. Dyn acts via the κ opioid receptor (KOR), and KOR is present in KNDy and GnRH neurons in sheep. KOR, similar to other G ...
21 CitationsSource
#1Robert L. Goodman (WVU: West Virginia University)H-Index: 46
#2Satoshi Okhura (Nagoya University)H-Index: 1
Last. Michael N. Lehman (UMMC: University of Mississippi Medical Center)H-Index: 1
view all 5 authors...
15 CitationsSource
#1Iain J. Clarke (Monash University)H-Index: 88
#2Qun Li (Monash University)H-Index: 12
Last. Robert P. Millar (UCT: University of Cape Town)H-Index: 94
view all 4 authors...
The Universities of Pretoria and Cape Town, South African Medical Research Council, and National Research Foundation. I.J.C. was funded by the National Health and Medical Research Council of Australia.
15 CitationsSource
#1Karolina Skorupskaite (Edin.: University of Edinburgh)H-Index: 7
#2Jyothis T. George (Warw.: University of Warwick)H-Index: 30
Last. Richard A. Anderson (Edin.: University of Edinburgh)H-Index: 116
view all 4 authors...
Context: Neurokinin B (NKB) is obligate for human puberty, but its role in adult female gonadotropin secretion and ovarian follicle growth is unknown. Objective: To investigate antagonism of NKB on pulsatile gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion and ovarian follicle development in healthy women. Design: Open investigation of the effects of a neurokinin-3 receptor (NK3R) antagonist (NK3Ra) vs a no-treatment control cycle. Setting: Clinical research facility....
29 CitationsSource
#1Karolina Skorupskaite (Edin.: University of Edinburgh)H-Index: 7
#2Jyothis T. George (Warw.: University of Warwick)H-Index: 30
Last. Richard A. Anderson (Edin.: University of Edinburgh)H-Index: 116
view all 5 authors...
The Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative STMTI and MRC grant G0701682 to RAA and RPM
15 CitationsSource
#1Jenny Clarkson (University of Otago)H-Index: 19
#2Su Young Han (University of Otago)H-Index: 8
Last. Allan E. Herbison (University of Otago)H-Index: 88
view all 11 authors...
Abstract The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exh...
138 CitationsSource
Cited By22
Newest
#1Shannon B. Z. Stephens (UCSD: University of California, San Diego)H-Index: 10
#2Alexander S. Kauffman (UCSD: University of California, San Diego)H-Index: 37
In females, ovarian estradiol (E2) exerts both negative and positive feedback regulation on the neural circuits governing reproductive hormone secretion, but the cellular and molecular mechanisms underlying this remain poorly understood. In rodents, ERα-expressing kisspeptin neurons in the hypothalamic anteroventral periventricular region (AVPV) are prime candidates to mediate E2 positive feedback induction of preovulatory GnRH and LH surges. E2 stimulates AVPV Kiss1 expression, but the full ext...
Source
#1Rajae Talbi (Harvard University)H-Index: 6
#2Kaitlin Ferrari (Brigham and Women's Hospital)
Last. Victor M. Navarro (Harvard University)H-Index: 57
view all 8 authors...
The alternation of the stimulatory action of the tachykinin neurokinin B (NKB) and the inhibitory action of dynorphin within arcuate (ARH) Kiss1 neurons has been proposed as the mechanism behind the generation of GnRH pulses through the pulsatile release of kisspeptin. However, we have recently documented that GnRH pulses still exist in gonadectomized mice in the absence of tachykinin signaling. Here, we document an increase in basal frequency and amplitude of LH pulses in intact male mice defic...
1 CitationsSource
#2Mauro S. B. Silva (university of lille)H-Index: 2
Last. Konstantina ChachlakiH-Index: 7
view all 4 authors...
Abstract Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating a GnRH pulse and surge remain a topic of debate. In this review we challenge the view of kisspeptin as an absolute “monarch”, and...
Source
#1Siew Hoong Yip (University of Otago)H-Index: 9
#2Xinhuai Liu (University of Otago)H-Index: 22
Last. Allan E. Herbison (University of Otago)H-Index: 88
view all 6 authors...
Acute stress is a potent suppressor of pulsatile LH secretion but the mechanisms through which corticotrophin-releasing hormone (CRH) neurons inhibit GnRH release remain unclear. The activation of paraventricular nucleus (PVN) CRH neurons with Cre-dependent hM3Dq in Crh-Cre female mice resulted in the robust suppression of pulsatile LH secretion. Channelrhodopsin (ChR2)-assisted circuit mapping revealed that PVN CRH neuron projections existed around kisspeptin neurons in the arcuate nucleus (ARN...
3 CitationsSource
#1Xinhuai Liu (University of Otago)H-Index: 22
#2Shel-Hwa Yeo (University of Cambridge)H-Index: 12
Last. Allan E. Herbison (University of Cambridge)H-Index: 88
view all 8 authors...
The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB), and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology...
5 CitationsSource
#1J Pape (UZH: University of Zurich)H-Index: 1
#2A E Herbison (University of Cambridge)H-Index: 1
Last. Brigitte Leeners (UZH: University of Zurich)H-Index: 20
view all 3 authors...
Background Prolonged amenorrhoea occurs as a consequence of functional hypothalamic amenorrhoea (FHA) which is most often induced by weight loss, vigorous exercise or emotional stress. Unfortunately, removal of these triggers does not always result in the return of menses. The prevalence and conditions underlying the timing of return of menses vary strongly and some women report amenorrhoea several years after having achieved and maintained normal weight and/or energy balance. A better understan...
2 CitationsSource
#1Siew Hoong Yip (University of Otago)H-Index: 9
#2Pauline Campos (University of Otago)H-Index: 3
Last. Allan E. Herbison (University of Otago)H-Index: 88
view all 5 authors...
The neural mechanisms generating pulsatile GnRH release from the median eminence (ME) remain unclear. Studies undertaken in the mouse demonstrate that GnRH neurons extend projections to the ME that have properties of both dendrites and axons, termed "dendrons," and that the kisspeptin neuron pulse generator targets these distal dendrons to drive pulsatile GnRH secretion. It presently remains unknown whether the GnRH neuron dendron exists in other species. We report here the generation of a knock...
4 CitationsSource
#1Selma F. Witchel (University of Pittsburgh)H-Index: 39
#2Tony M. Plant (University of Pittsburgh)H-Index: 65
Abstract null null Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in...
Source
#1Lourdes A Esparza (UCSD: University of California, San Diego)H-Index: 3
#1Lourdes A. Esparza (UCSD: University of California, San Diego)H-Index: 7
Last. Alexander S. Kauffman (UCSD: University of California, San Diego)H-Index: 37
view all 4 authors...
Androgens can affect the reproductive axis of both sexes. In healthy women, as in men, elevated exogenous androgens decrease gonad function and lower gonadotropin levels; such circumstances occur with anabolic steroid abuse or in transgender men (genetic XX individuals) taking androgen supplements. The neuroendocrine mechanisms by which endogenous or exogenous androgens regulate gonadotropin release, including aspects of pulsatile luteinizing hormone (LH) secretion, remain unknown. Because anima...
Source
#1Michael J. D'Occhio (USYD: University of Sydney)H-Index: 26
#2Giuseppe Campanile (University of Naples Federico II)H-Index: 24
Last. Pietro Sampaio Baruselli (USP: University of São Paulo)H-Index: 50
view all 3 authors...
Kisspeptin (KISS1) is encoded by the KISS1 gene and was initially found to be a repressor of metastasis. Natural mutations in the KISS1 receptor gene (KISS1R) were subsequently shown be associated with idiopathic hypothalamic hypogonadism and impaired puberty. This led to interest in the role of KISS1 in reproduction. It was established that KISS1 had a fundamental role in the control of GnRH secretion. KISS1 neurons have receptors for leptin and estrogen receptor α (ERα) which places KISS1 at t...
3 CitationsSource