scholarly journals NKB Signaling in the Medial Amygdala Stimulates Gonadotropin Release in a Kisspeptin-Independent Manner in Female Mice

2018 ◽  
Author(s):  
Chrysanthi Fergani ◽  
Silvia León ◽  
Stephanie L. Padilla ◽  
Anne MJ Verstegen ◽  
Richard D. Palmiter ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Reproductive Function ◽  
Medial Amygdala ◽  
Regulatory Pathway ◽  
Neurokinin B ◽  
Independent Manner ◽  
Stimulatory Action ◽  
Gnrh Release ◽  
Lh Release

AbstractNeurokinin B (NKB) signaling is critical for reproduction in all studied species. The existing consensus is that NKB induces GnRH release via kisspeptin (Kiss1) stimulation in the arcuate nucleus. However, the stimulatory action of NKB is dependent on circulating estrogen (E2) levels, without which, NKB inhibits LH release. Importantly, the evidence supporting the kisspeptin-dependent role of NKB, derives from models of persistent hypogonadal state [e.g. Kiss1r knockout (KO) mice], with reduced E2 levels. Here, we demonstrate that in the presence of E2, NKB signaling induces LH release in a kisspeptin-independent manner. Moreover, senktide (NKB receptor agonist) delivery to the medial amygdala (MeA) increases LH in E2-treated Kiss1 KO females (but not males or sham-treated females) similar to controls, and thus, this increase is independent of Kiss1 neurons. These results document a novel kisspeptin-independent regulatory pathway of reproductive function in females mediated by NKB-responsive neurons in the MeA.

scholarly journals NKB signaling in the posterodorsal medial amygdala stimulates gonadotropin release in a kisspeptin-independent manner in female mice

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Chrysanthi Fergani ◽  
Silvia Leon ◽  
Stephanie L Padilla ◽  
Anne MJ Verstegen ◽  
Richard D Palmiter ◽  
...  
Keyword(s):  
Reproductive Function ◽  
Editorial Note ◽  
Medial Amygdala ◽  
Independent Manner ◽  
Stimulatory Action ◽  
Knock Out ◽  
Gnrh Release ◽  
Lh Release ◽  
Receptor Neurons

Neurokinin B (NKB) signaling is critical for reproduction in all studied species. The existing consensus is that NKB induces GnRH release via kisspeptin (Kiss1) stimulation in the arcuate nucleus. However, the stimulatory action of NKB is dependent on circulating estrogen (E2) levels, without which, NKB inhibits luteinizing hormone (LH) release. Importantly, the evidence supporting the kisspeptin-dependent role of NKB, derives from models of persistent hypogonadal state [e.g. Kiss1r knock-out (KO) mice], with reduced E2 levels. Here, we demonstrate that in the presence of E2, NKB signaling induces LH release in a kisspeptin-independent manner through the activation of NK3R (NKB receptor) neurons in the posterodorsal medial amygdala (MePD). Importantly, we show that chemogenetic activation of MePD Kiss1 neurons induces LH release, however, the stimulatory action of NKB in this area is Kiss1 neuron-independent. These results document the existence of two independent neuronal circuitries within the MePD that regulate reproductive function in females.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals The Integrated Hypothalamic Tachykinin-Kisspeptin System as a Central Coordinator for Reproduction

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 627-637 ◽  
Author(s):  
Víctor M. Navarro ◽  
Martha A. Bosch ◽  
Silvia León ◽  
Serap Simavli ◽  
Cadence True ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Neurokinin A ◽  
Ventromedial Nucleus ◽  
Central Regulation ◽  
Neurokinin B ◽  
Gonadotropin Release ◽  
Neurokinin Receptor ◽  
The Family ◽  
Gnrh Release ◽  
Lh Release

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r−/− mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.

scholarly journals Neurokinin B Stimulates GnRH Release in the Male Monkey (Macaca mulatta) and Is Colocalized with Kisspeptin in the Arcuate Nucleus

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4494-4503 ◽  
Author(s):  
Suresh Ramaswamy ◽  
Stephanie B. Seminara ◽  
Barkat Ali ◽  
Philippe Ciofi ◽  
Nisar A. Amin ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Human Genetics ◽  
Intermittent Infusion ◽  
Repetitive Stimulation ◽  
Neurokinin B ◽  
Axonal Projections ◽  
Pulsatile Gnrh ◽  
Gnrh Release ◽  
Lh Release ◽  
Stimulation Of

Human genetics indicate that kisspeptin and neurokinin B (NKB) signaling are necessary for generating pulsatile LH release and therefore for initiation of puberty and maintaining gonadal function. In the present study, male monkeys were employed to examine 1) whether activation of the NKB receptor (NK3R) is associated with GnRH release, and 2) hypothalamic localization of these peptides using immunofluorescence histochemistry. Agonadal juveniles, in which pituitary responsiveness to GnRH was heightened by GnRH priming, were employed to indirectly examine GnRH-releasing actions of NK3R and kisspeptin receptor agonists by tracking LH after their iv injection. Castrated adults were used for immunohistochemistry. Single iv injections of NKB or senktide (an NK3R agonist) elicited robust LH discharges that were abolished by GnRH receptor antagonism (acyline) confirming the ligands’ hypothalamic action. Intermittent infusion of senktide (1-min pulse every hour for 4 h), in contrast to that of kisspeptin, failed to sustain pulsatile GnRH release. Repetitive senktide injections did not compromise the GnRH-releasing action of kisspeptin. NKB and kisspeptin were colocalized in perikarya of the arcuate nucleus and in axonal projections to the median eminence, confirming earlier findings in sheep. These results are consistent with the human genetics, and indicate that although brief activation of NK3R stimulates GnRH release, repetitive stimulation of this pathway, in contrast to that of kisspeptin receptor, fails to sustain pulsatile GnRH release. In addition, the data provide a platform for future elucidation of the interactions between NKB and kisspeptin that are required for generating pulsatile GnRH release in primates.

scholarly journals Redundancy in the central tachykinin systems safeguards puberty onset and fertility

2018 ◽  
Author(s):  
Silvia León ◽  
Chrysanthi Fergani ◽  
Rajae Talbi ◽  
Serap Simavli ◽  
Caroline A. Maguire ◽  
...  
Keyword(s):  
Substance P ◽  
Reproductive Success ◽  
Sex Steroids ◽  
Delayed Puberty ◽  
Neurokinin A ◽  
Neurokinin B ◽  
Female Mice ◽  
Gnrh Release ◽  
Lh Release ◽  
Puberty Onset

ABSTRACTThe tachykinin neurokinin B (NKB, Tac2) is critical for GnRH release. NKB signaling deficiency leads to infertility in humans. However, some patients reverse this hypogonadism resembling the fertile phenotype of Tac2KO and Tacr3KO (encoding NKB receptor, NK3R) mice despite the absence of NKB signaling. Here, we demonstrate that in the absence of NKB signaling, other tachykinins (substance P and neurokinin A [NKA], encoded by Tac1) may take over to preserve fertility. The complete absence of tachykinins in Tac1/Tac2KO mice leads to delayed puberty onset in both sexes and infertility in 80% of females (but not males), in contrast to the 100% fertile phenotype of Tac1KO and Tac2KO mice separately. Furthermore, we demonstrate that NKA controls puberty onset and LH release through NKB-independent mechanisms in the presence of sex steroids and NKB-dependent mechanisms in their absence. In summary, tachykinins interact in a coordinated manner to ensure reproductive success in female mice.

scholarly journals Characterization of the Role of NKA in the Control of Puberty Onset and Gonadotropin Release in the Female Mouse

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2453-2463 ◽  
Author(s):  
Silvia León ◽  
Chrysanthi Fergani ◽  
Rajae Talbi ◽  
Serap Simavli ◽  
Caroline A Maguire ◽  
...  
Keyword(s):  
Sex Steroids ◽  
Neurokinin A ◽  
Central Control ◽  
Gnrh Release ◽  
Lh Release ◽  
Timing Of Puberty ◽  
Puberty Onset ◽  
Lh Secretion

Abstract The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.

scholarly journals KNDy Neurons Modulate the Magnitude of the Steroid-Induced Luteinizing Hormone Surges in Ovariectomized Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4200-4213 ◽  
Author(s):  
Cleyde V. Helena ◽  
Natalia Toporikova ◽  
Bruna Kalil ◽  
Andrea M. Stathopoulos ◽  
Veronika V. Pogrebna ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Arcuate Nucleus ◽  
Ovariectomized Rats ◽  
Neurokinin B ◽  
Lh Surge ◽  
Neuronal Populations ◽  
Lh Release ◽  
Positive And Negative Feedback ◽  
Kndy Neurons ◽  
Lh Secretion

Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.

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 PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

2018 ◽  
Author(s):  
Rachel A. Ross ◽  
Silvia León ◽  
Joseph C. Madara ◽  
Danielle Schafer ◽  
Chrysanthi Fergani ◽  
...  
Keyword(s):  
Reproductive Function ◽  
Delayed Puberty ◽  
Targeted Deletion ◽  
Pituitary Adenylate Cyclase ◽  
Genetic Cross ◽  
Gnrh Release ◽  
Lh Release ◽  
Puberty Onset ◽  
Disclosure Statement ◽  
Hypothalamic Level

AbstractPituitary adenylate cyclase activating polypeptide (PACAP) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with PACAPfl/flmice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new, sex-specific role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction.Disclosure statementThe authors have nothing to disclose.

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.

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