scholarly journals 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 ◽  
Vol 10 ◽  
Author(s):  
Margaritis Voliotis ◽  
Xiao Feng Li ◽  
Ross Alexander De Burgh ◽  
Geffen Lass ◽  
Deyana Ivanova ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Reproductive Function ◽  
Pulse Generation ◽  
Ovarian Cycle ◽  
Gonadal Steroids ◽  
Pulsatile Gnrh ◽  
Gnrh Release ◽  
Kndy Neurons ◽  
Stimulation Of

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

scholarly journals Modulation of pulsatile GnRH dynamics across the ovarian cycle: the role of excitability within the arcuate kisspeptin network

2021 ◽  
Author(s):  
Margaritis Voliotis ◽  
Xiao Feng Li ◽  
Ross De Burgh ◽  
Geffen Lass ◽  
Deyana Ivanova ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Pulse Generation ◽  
Ovarian Cycle ◽  
Gonadal Steroids ◽  
Pulsatile Gnrh ◽  
Gnrh Release ◽  
Kndy Neurons ◽  
Stimulation Of

AbstractPulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons’ signalling properties. However, the precise mechanism of regulation remains mostly unknown. Here we investigate these mechanisms using a combination of mathematical and in-vivo approaches. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. Our mathematical modelling suggests that this differential effect is due to well-orchestrated changes in neuropeptide signalling and the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in the arcuate nucleus in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH secretion dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

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

F1000Research ◽  
2020 ◽  
Vol 8 ◽  
pp. 982 ◽  
Author(s):  
Tony M. Plant
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Generation ◽  
Luteinizing Hormone Secretion ◽  
Gnrh Release ◽  
Exciting Time ◽  
Kndy Neurons ◽  
Hypophysial Portal

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.

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

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 982 ◽  
Author(s):  
Tony M. Plant
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Generation ◽  
Luteinizing Hormone Secretion ◽  
Gnrh Release ◽  
Exciting Time ◽  
Kndy Neurons ◽  
Hypophysial Portal

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.

scholarly journals Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 752-763 ◽  
Author(s):  
Kristen A. Ruka ◽  
Laura L. Burger ◽  
Suzanne M. Moenter
Keyword(s):  
Estrogen Receptor ◽  
Firing Pattern ◽  
Pulse Generator ◽  
Brain Slices ◽  
Gonadal Steroids ◽  
Gnrh Neuron ◽  
Male Mice ◽  
Neurokinin B ◽  
Neuron Firing ◽  
Kndy Neurons

Abstract Gonadal steroids regulate the pattern of GnRH secretion. Arcuate kisspeptin (kisspeptin, neurokinin B, and dynorphin [KNDy]) neurons may convey steroid feedback to GnRH neurons. KNDy neurons increase action potential firing upon the activation of neurokinin B receptors (neurokinin-3 receptor [NK3R]) and decrease firing upon the activation of dynorphin receptors (κ-opioid receptor [KOR]). In KNDy neurons from intact vs castrated male mice, NK3R-mediated stimulation is attenuated and KOR-mediated inhibition enhanced, suggesting gonadal secretions are involved. Estradiol suppresses spontaneous GnRH neuron firing in male mice, but the mediators of the effects on firing in KNDy neurons are unknown. We hypothesized the same gonadal steroids affecting GnRH firing pattern would regulate KNDy neuron response to NK3R and KOR agonists. To test this possibility, extracellular recordings were made from KNDy neurons in brain slices from intact, untreated castrated or castrated adult male mice treated in vivo with steroid receptor agonists. As observed previously, the stimulation of KNDy neurons by the NK3R agonist senktide was attenuated in intact vs castrated mice and suppression by dynorphin was enhanced. In contrast to observations of steroid effects on the GnRH neuron firing pattern, both estradiol and DHT suppressed senktide-induced KNDy neuron firing and enhanced the inhibition caused by dynorphin. An estrogen receptor-α agonist but not an estrogen receptor-β agonist mimicked the effects of estradiol on NK3R activation. These observations suggest the steroid modulation of responses to activation of NK3R and KOR as mechanisms for negative feedback in KNDy neurons and support the contribution of these neurons to steroid-sensitive elements of a GnRH pulse generator.

scholarly journals Suppression of the GnRH Pulse Generator by Neurokinin B Involves a κ-Opioid Receptor-Dependent Mechanism

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4894-4904 ◽  
Author(s):  
P. Grachev ◽  
X. F. Li ◽  
J. S. Kinsey-Jones ◽  
A. L. di Domenico ◽  
R. P. Millar ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Neurokinin B ◽  
Kndy Neurons ◽  
Lh Secretion ◽  
Dose Dependent

Abstract Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17β-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.

scholarly journals Menopausal Increases in Pulsatile Gonadotropin-Releasing Hormone Release in a Nonhuman Primate (Macaca mulatta)

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4653-4659 ◽  
Author(s):  
Andrea C. Gore ◽  
Bret M. Windsor-Engnell ◽  
Ei Terasawa
Keyword(s):  
Reproductive Function ◽  
Pulse Frequency ◽  
Follicular Phase ◽  
Menopausal Transition ◽  
Primate Species ◽  
Primary Role ◽  
Pulsatile Gnrh ◽  
Direct Demonstration ◽  
Gnrh Release ◽  
Early Follicular Phase

Abstract Reproductive function in all vertebrates is controlled by the circhoral release of the neuropeptide, GnRH, into the portal capillary system leading to the anterior pituitary. Despite its primary role in sexual maturation and the maintenance of adult reproductive function, changes in the concentrations and pattern of GnRH release have not yet been reported in any primate species during the menopausal transition and postmenopause. Such knowledge is essential for ascertaining both the mechanisms for, and consequences of, the menopausal process. Here we used a push-pull perfusion method to measure and compare the parameters of pulsatile GnRH release in adult rhesus monkeys at 8.4 ± 1.5 yr (young adult females, early follicular phase, n = 6) and 28.8 ± 0.3 yr (aged females, n = 4, of which two monkeys were in the menopausal transition, and two were postmenopausal). Our results demonstrate that: 1) GnRH release is pulsatile in both young and aged monkeys; 2) mean concentrations of GnRH increase during reproductive aging; and 3) GnRH pulse frequency does not differ between aged monkeys and young monkeys in the early follicular phase. We conclude that not only do GnRH neurons have the continued capacity to release GnRH in a pulsatile manner but also they can do so with enhanced GnRH levels in aged primates. To our knowledge, this is the first direct demonstration of elevated pulsatile GnRH concentrations in a primate species during reproductive senescence, a result that may have implications for menopausal symptoms.

Neuroendocrine Mechanisms Regulating Reproductive Transition in the Ruminant Female: Is KNDy Required?

2021 ◽  
Vol 99 (Supplement_2) ◽  
pp. 22-23
Author(s):  
Gary L Williams
Keyword(s):  
Signaling Pathways ◽  
Pulse Generator ◽  
Pubertal Development ◽  
Convincing Evidence ◽  
Pulse Generation ◽  
Pharmacological Agents ◽  
Medial Basal Hypothalamus ◽  
Cellular Origin ◽  
Neuroendocrine Mechanisms ◽  
Kndy Neurons

Abstract States of reproductive transition in female livestock represent important and economically significant periods of physiological change that have major impacts on the efficiency and success of breeding and production programs. These include, but are not limited to, the process of sexual maturation, postpartum resumption of ovarian cycles, and cyclical recrudescence in seasonal breeding species. Over the last four decades, our laboratory has focused primarily on determining the fundamental neuroendocrine mechanisms controlling states of reproductive transition in bovine and equine models, and applying principals learned to develop managerial approaches for positive intervention. The objectives of this presentation are to briefly review our understanding of external and internal signaling pathways that regulate two of these transitional states in the bovine female, postpartum resumption of ovulatory cycles and pubertal development. The focus will be to consider contrasts and commonalities of hypothalamic-pituitary signaling pathways that govern the temporal trajectories of these processes, with particular emphasis on those pathways that modulate the GnRH pulse generator. Notably (and until recently), the pulse generator has been a poorly defined “black box” with respect to its cellular origin and neurochemical character. Thus, the synchronous pattern of GnRH neuronal depolarization, multiunit electrical activity, and release of GnRH for the control of gonadotropins have been accepted as intrinsic features of GnRH neurons themselves. However, the identification of the neuropeptide kisspeptin in 1996, and more recently (2007) the description of a specialized population of kisspeptin-secreting neurons in the medial basal hypothalamus, termed KNDy neurons, have provided convincing evidence for an extrinsic source of pulse generation within the arcuate/infundibular region. How do KNDy neurons serve in this function, what is their role in transducing environmental, nutritional, and behavioral signals during transitional states, and what is the potential for neuropeptides of KNDy neuron origin to serve as pharmacological agents to control reproduction?

scholarly journals Regulation of GnRH pulsatility in ewes

Reproduction ◽  
2018 ◽  
Vol 156 (3) ◽  
pp. R83-R99 ◽  
Author(s):  
Casey C Nestor ◽  
Michelle N Bedenbaugh ◽  
Stanley M Hileman ◽  
Lique M Coolen ◽  
Michael N Lehman ◽  
...  
Keyword(s):  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Neural Systems ◽  
Physiological Regulation ◽  
Gnrh Secretion ◽  
Lack Of Information ◽  
Gnrh Release ◽  
Kndy Neurons ◽  
Dynorphin Release

Early work in ewes provided a wealth of information on the physiological regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by internal and external inputs. Identification of the neural systems involved, however, was limited by the lack of information on neural mechanisms underlying generation of GnRH pulses. Over the last decade, considerable evidence supported the hypothesis that a group of neurons in the arcuate nucleus that contain kisspeptin, neurokinin B and dynorphin (KNDy neurons) are responsible for synchronizing secretion of GnRH during each pulse in ewes. In this review, we describe our current understanding of the neural systems mediating the actions of ovarian steroids and three external inputs on GnRH pulsatility in light of the hypothesis that KNDy neurons play a key role in GnRH pulse generation. In breeding season adults, estradiol (E2) and progesterone decrease GnRH pulse amplitude and frequency, respectively, by actions on KNDy neurons, with E2decreasing kisspeptin and progesterone increasing dynorphin release onto GnRH neurons. In pre-pubertal lambs, E2inhibits GnRH pulse frequency by decreasing kisspeptin and increasing dynorphin release, actions that wane as the lamb matures to allow increased pulsatile GnRH secretion at puberty. Less is known about mediators of undernutrition and stress, although some evidence implicates kisspeptin and dynorphin, respectively, in the inhibition of GnRH pulse frequency by these factors. During the anoestrus, inhibitory photoperiod acting via melatonin activates A15 dopaminergic neurons that innervate KNDy neurons; E2increases dopamine release from these neurons to inhibit KNDy neurons and suppress the frequency of kisspeptin and GnRH release.

scholarly journals Evidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe

Endocrinology ◽  
2018 ◽  
Vol 159 (9) ◽  
pp. 3187-3199 ◽  
Author(s):  
Peyton W Weems ◽  
Lique M Coolen ◽  
Stanley M Hileman ◽  
Steven Hardy ◽  
Rick B McCosh ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Third Ventricle ◽  
Pulse Generation ◽  
G Protein Coupled Receptors ◽  
Neurokinin B ◽  
Gnrh Secretion ◽  
Pulsatile Gnrh ◽  
Gnrh Neurons ◽  
Kndy Neurons ◽  
G Protein Coupled

Abstract 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 protein–coupled receptors, are internalized after exposure to ligand, and thus internalization can be used as a marker of endogenous Dyn release. Thus, we hypothesized that KOR will be internalized at pulse termination in both KNDy and GnRH neurons. To test this hypothesis, GnRH pulses were induced in gonad-intact anestrous ewes by injection of neurokinin B (NKB) into the third ventricle and animals were euthanized at times of either pulse onset or termination. NKB injections produced increased internalization of KOR within KNDy neurons during both pulse onset and termination. In contrast, KOR internalization into GnRH neurons was seen only during pulse termination, and only in GnRH neurons within the mediobasal hypothalamus (MBH). Overall, our results indicate that Dyn is released onto KNDy cells at the time of pulse onset, and continues to be released during the duration of the pulse. In contrast, Dyn is released onto MBH GnRH neurons only at pulse termination and thus actions of Dyn upon KNDy and GnRH cell bodies may be critical for pulse termination.

scholarly journals Indirect assessment of pulsatile gonadotropin-releasing hormone release in agonadal prepubertal rhesus monkeys (Macaca mulatta)

1999 ◽  
Vol 160 (1) ◽  
pp. 35-41 ◽  
Author(s):  
KJ Suter ◽  
CR Pohl ◽  
TM Plant
Keyword(s):  
Pulse Generator ◽  
Intermittent Infusion ◽  
Open Loop ◽  
Remote Access ◽  
Striking Difference ◽  
Major Purpose ◽  
Venous Circulation ◽  
Pulsatile Gnrh ◽  
Gnrh Release ◽  
Lh Secretion

The major purpose of this study was to characterize the open-loop frequency of pulsatile GnRH release in the female rhesus monkey at an age (15-20 months) when the prepubertal restraint on the hypothalamic-pituitary axis is maximally imposed. Additionally, evidence for pulsatile GnRH release in agonadal males of comparable age was also sought. Episodic LH secretion from the pituitary was used as an indirect index of GnRH discharges. In order to maximize the sensitivity of this in situ bioassay, the responsiveness of the pituitary gonadotrophs was usually first heightened by an i.v. intermittent infusion of the synthetic peptide. Monkeys (five females, three males) were castrated between 9 and 14 months of age, implanted with indwelling venous catheters, fitted with nylon jackets and housed in specialized cages that permitted remote access to the venous circulation with minimal restraint and without interruption of the light-darkness cycle. In females, LH secretion was generally assessed at 20-day intervals during alternate nighttime (1900-0200 h) and daytime (0700-1400 h) windows. In males, LH was assessed less frequently and only at night. The mean frequency of pulsatile LH release in agonadal prepubertal females was 4 pulses/7 h during the night and 2 pulses/7 h during the day. These findings indicate that, prior to puberty in the female monkey, the GnRH pulse generator operates at a relatively slow frequency and is subjected to diurnal modulation. In males, evidence for robust pulsatile GnRH release was not observed. The striking difference in activity of the GnRH pulse generator in agonadal prepubertal male and female monkeys reinforces the view that the ontogeny of the hypothalamic drive to the pituitary-gonadal axis in higher primates, including man, is sexually differentiated.

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