scholarly journals Interactions between neurotensin and GnRH neurons in the positive feedback control of GnRH/LH secretion in the mouse

2010 ◽  
Vol 298 (1) ◽  
pp. E80-E88 ◽  
Author(s):  
Heather M. Dungan Lemko ◽  
Roxana Naderi ◽  
Valeriya Adjan ◽  
Lothar H. Jennes ◽  
Victor M. Navarro ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Neural Circuits ◽  
Direct Role ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Double Label ◽  
Lh Secretion

In female mammals, increased ovarian estradiol (E2) secretion triggers GnRH release from neurons in the basal forebrain, which drives LH secretion from the pituitary and subsequently induces ovulation. However, the neural circuits that activate this preovulatory GnRH/LH surge remain unidentified. Neurotensin is expressed in neurons of the anteroventral periventricular nucleus (AVPV), a region thought to be critical for generating the preovulatory GnRH/LH surge. E2 induces neurotensin ( Nts) gene expression in this region, and blockade of neurotensin signaling reduces the LH surge in the rat. We postulated that neurotensin signaling plays a similar role in generating the E2-induced GnRH/LH surge in mice. We used in situ hybridization (ISH) to determine whether E2 induces Nts expression in the mouse and found evidence to support this proposition. Next, we determined that the neurotensin receptor (Ntsr2) is present in many GnRH-expressing neurons. Since the kisspeptin gene ( Kiss1) is expressed in the AVPV and is responsive to E2, we predicted that some neurons in this region express both Kiss1 and Nts; however, by double-label ISH, we observed no coexpression of the two mRNAs. We also postulated that Nts mRNA expression would increase in parallel with the E2-induced LH surge and that the central (icv) administration of neurotensin would stimulate LH secretion and activation of GnRH neurons but found no evidence to support either of these hypotheses. Together, these findings suggest that, although neurotensin neurons in the AVPV are targets for regulation by E2, neurotensin does not appear to play a direct role in generating the GnRH/LH surge in the mouse.

scholarly journals Development, Sex Steroid Regulation, and Phenotypic Characterization of RFamide-Related Peptide (Rfrp) Gene Expression and RFamide Receptors in the Mouse Hypothalamus

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1827-1840 ◽  
Author(s):  
Matthew C. Poling ◽  
Joshua Kim ◽  
Sangeeta Dhamija ◽  
Alexander S. Kauffman
Keyword(s):  
In Situ Hybridization ◽  
Estrogen Receptor Α ◽  
Cell Number ◽  
Phenotypic Characterization ◽  
Related Peptide ◽  
Adult Mice ◽  
Gnrh Neurons ◽  
Double Label ◽  
Hormonal Milieu

Arginine-phenylalanine-amide (RFamide)-related peptide 3 (RFRP-3, encoded by the Rfrp gene) is the mammalian ortholog of gonadotropin-inhibiting hormone and can inhibit GnRH neuronal activity and LH release. However, the development and regulation of the RFRP-3 system in both sexes is poorly understood. Using in situ hybridization, we examined changes in Rfrp-expressing neurons in mice of both sexes during development and under different adulthood hormonal milieus. We found no sex differences in Rfrp expression or cell number in adult mice. Interestingly, we identified two interspersed subpopulations of Rfrp cells (high Rfrp-expressing, HE; low Rfrp-expressing, LE), which have unique developmental and steroidal regulation characteristics. The number of LE cells robustly decreases during postnatal development, whereas HE cell number increases significantly before puberty. Using Bax knockout mice, we determined that the dramatic developmental decrease in LE Rfrp cells is not due primarily to BAX-dependent apoptosis. In adults, we found that estradiol and testosterone moderately repress Rfrp expression in both HE and LE cells, whereas the nonaromatizable androgen dihydrotestosterone has no effect. Using double-label in situ hybridization, we determined that approximately 25% of Rfrp neurons coexpress estrogen receptor-α in each sex, whereas Rfrp cells do not readily express androgen receptor in either sex, regardless of hormonal milieu. Lastly, when we looked at RFRP-3 receptors, we detected some coexpression of Gpr147 but no coexpression of Gpr74 in GnRH neurons of both intact and gonadectomized males and females. Thus, RFRP-3 may exert its effects on reproduction either directly, via Gpr147 in a subset of GnRH neurons, and/or indirectly, via upstream regulators of GnRH.

scholarly journals Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 363-374 ◽  
Author(s):  
Raphael E. Szawka ◽  
Maristela O. Poletini ◽  
Cristiane M. Leite ◽  
Marcelo P. Bernuci ◽  
Bruna Kalil ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Preoptic Area ◽  
Lh Surge ◽  
Ovx Rats ◽  
Selective Lesion ◽  
Periventricular Nucleus ◽  
Reverse Microdialysis ◽  
Fos Expression ◽  
Lh Secretion

The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.

scholarly journals Pup removal suppresses estrogen-induced surges of LH secretion and activation of GnRH neurons in lactating rats

2006 ◽  
Vol 191 (1) ◽  
pp. 339-348 ◽  
Author(s):  
Atsushi Fukushima ◽  
Ping Yin ◽  
Maho Ishida ◽  
Nobuhiro Sugiyama ◽  
Jun Arita
Keyword(s):  
Third Ventricle ◽  
Acute Effect ◽  
Suppressive Effect ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Indwelling Catheter ◽  
Lh Surge ◽  
Gnrh Neurons ◽  
Double Immunohistochemical Staining ◽  
Lh Secretion

During lactation, the suckling stimulus exerts profound influences on neuroendocrine regulation in nursing rats. We examined the acute effect of pup removal on the estrogen-induced surge of LH secretion in ovariectomized lactating rats. Lactating and nonlactating cyclic female rats were given an estradiol-containing capsule after ovariectomy, and blood samples were collected through an indwelling catheter for serum LH determinations. In lactating, freely suckled ovariectomized rats, estrogen treatment induced an afternoon LH surge with a magnitude and timing comparable to those seen in nonlactating rats. Removal of pups from the lactating rats at 0900, 1100, or 1300 h, but not at 1500 h, suppressed the estrogen-induced surge that normally occurs in the afternoon of the same day. The suppressive effect of pup removal at 0900 h was completely abolished when the pups were returned by 1400 h. In contrast, pup removal was ineffective in abolishing the stimulatory effect of progesterone on LH surges. Double immunohistochemical staining for gonadotropin-releasing hormone (GnRH) and c-Fos, a marker for neuronal activation, revealed a decrease, concomitantly with the suppression of LH surges, in the number of c-Fos-immunoreactive GnRH neurons in the preoptic regions of nonsuckled rats. An LH surge was restored in nonsuckled rats when 0.1 μg oxytocin was injected into the third ventricle three times at 1-h intervals during pup removal. These results suggest that the GnRH surge generator of lactating rats requires the suckling stimulus that is not involved in nonlactating cyclic female rats.

scholarly journals Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 with Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 1007-1013 ◽  
Author(s):  
Tony M. Plant ◽  
Suresh Ramaswamy ◽  
Meloni J. DiPietro
Keyword(s):  
G Protein ◽  
Concomitant Treatment ◽  
Secondary Effects ◽  
G Protein Coupled Receptor ◽  
Gnrh Release ◽  
Dependent Signal ◽  
Lh Release ◽  
Lh Secretion ◽  
G Protein Coupled

The purpose of the present study was to further examine the hypothesis that activation of G protein-coupled receptor 54 (GPR54) signaling at the end of the juvenile phase of primate development is responsible for initiation of gonadarche and the onset of puberty. Accordingly, we determined whether repetitive iv administration of the GPR54 receptor agonist kisspeptin-10 (2 μg as a brief 1-min infusion once every hour for 48 h) to the juvenile male rhesus monkey would prematurely elicit sustained, pulsatile release of hypothalamic GnRH, the neuroendocrine trigger for gonadarche. GnRH release was monitored indirectly by measuring LH secretion from the in situ pituitary, the GnRH responsiveness of which had been heightened before the experiment with an intermittent iv infusion of synthetic GnRH. Agonadal animals (n = 4) were employed to eliminate any confounding and secondary effects of changing feedback signals from the testis. The first brief infusion of kisspeptin-10 evoked an LH discharge that mimicked those produced by GnRH priming, and this was followed by a train of similar LH discharges in response to hourly activation of GPR54 by repetitive kisspeptin-10 administration. Concomitant treatment with a GnRH receptor antagonist, acyline, abolished kisspeptin-10-induced LH release. Repetitive kisspeptin-10 administration also provided a GnRH-dependent signal to FSH secretion. These findings are consistent with the notion that, in primates, the transition from the juvenile (attenuated GnRH release) to pubertal (robust GnRH release) state is controlled by activation of GPR54 resulting from increased expression of hypothalamic KiSS-1 and release of kisspeptin in this region of the brain.

Circadian Function in Multiple Cell Types Is Necessary for Proper Timing of the Preovulatory LH Surge

2019 ◽  
Vol 34 (6) ◽  
pp. 622-633 ◽  
Author(s):  
Eric L. Bittman
Keyword(s):  
Cell Types ◽  
Noticeable Effect ◽  
Lh Surge ◽  
Conditional Deletion ◽  
Proper Timing ◽  
Circadian Control ◽  
Gnrh Neurons ◽  
Multiple Cell ◽  
Locomotor Rhythms ◽  
Lh Secretion

The timing of the preovulatory surge of luteinizing hormone (LH), which occurs on the evening of proestrus in female mice, is determined by the circadian system. The identity of cells that control the phase of the LH surge is unclear: evidence supports a role of arginine vasopressin (AVP) cells of the suprachiasmatic nucleus (SCN), but it is not known whether vasopressinergic neurons are necessary or sufficient to account for circadian control of ovulation. Among other cell types, evidence also suggests important roles of circadian function of kisspeptin cells of the anteroventral periventricular nucleus (AvPV) and gonadotropin-releasing hormone (GnRH) neurons of the preoptic area (POA), whose discharge is immediately responsible for the discharge of LH from the anterior pituitary. The present studies used an ovariectomized, estradiol-treated preparation to determine critical cell types whose clock function is critical to the timing of LH secretion. As expected, the LH surge occurred at or shortly after ZT12 in control mice. In further confirmation of circadian control, the surge was advanced by 2 h in tau mutant animals. The timing of the surge was altered to varying degrees by conditional deletion of Bmal1 in AVPCre, KissCreBAC, and GnRHCreBAC mice. Excision of the mutant Cnsk1e (tau) allele in AVP neurons resulted in a reversion of the surge to the ZT12. Conditional deletion of Bmal1 in Kiss1 or GnRH neurons had no noticeable effect on locomotor rhythms, but targeting of AVP neurons produced variable effects on circadian period that did not always correspond to changes in the phase of LH secretion. The results indicate that circadian function in multiple cell types is necessary for proper timing of the LH surge.

scholarly journals Genetic Deletion of Esr1 in the Mouse Preoptic Area Disrupts the LH Surge and Estrous Cyclicity

Endocrinology ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Robert Porteous ◽  
Allan E Herbison
Keyword(s):  
Estrogen Receptor ◽  
Third Ventricle ◽  
Estrogen Receptor Α ◽  
Adeno Associated Virus ◽  
Estrous Cycles ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Estrous Cyclicity ◽  
Periventricular Area

Abstract Estrogen receptor α (ESR1) is critical for the generation of the preovulatory LH surge. Experiments in rodents have indicated a role for neurons located in the anteroventral periventricular area and preoptic periventricular nucleus [termed the rostral periventricular area of the third ventricle (RP3V)] in surge generation. In the current study, we aimed to examine whether ESR1 expressed by RP3V neurons was necessary for the LH surge. The estrous cycles of mice with estrogen receptor α (Esr1) exon 3 flanked by LoxP sites (Esr1 flox) and controls were monitored before and after bilateral stereotactic injection of adeno-associated virus encoding Cre recombinase into the RP3V. This resulted in 84% and 72% decreases in ESR1-immunoreactive cell numbers in the anteroventral periventricular area and preoptic periventricular nucleus, respectively, with no changes in the arcuate nucleus. Beginning three weeks after the adeno-associated virus injection, Esr1 flox mice began to show a loss of estrous cyclicity going, primarily, into constant estrus. Wild-type mice and Esr1 flox mice with injections outside the RP3V or unilateral ablations of ESR1 continued to exhibit normal estrous cycles. Mice were then gonadectomized and given an estradiol replacement regimen to generate the LH surge. This resulted in an absence of cFOS expression in GnRH neurons (1 ± 1% vs 28 ± 4% of GnRH neurons; P < 0.01) and markedly reduced LH surge levels (2.5 ± 0.6 vs 9.1 ± 1.0 ng/mL; P < 0.01) in Esr1 flox mice compared with controls. These results demonstrate that neurons expressing ESR1 within the RP3V are critical for the generation of the LH surge and estrous cyclicity in the mouse.

scholarly journals Circadian Control of the Female Reproductive Axis Through Gated Responsiveness of the RFRP-3 System to VIP Signaling

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2608-2618 ◽  
Author(s):  
Kimberly A. Russo ◽  
Janet L. La ◽  
Shannon B. Z. Stephens ◽  
Matthew C. Poling ◽  
Namita A. Padgaonkar ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Neuronal System ◽  
Ovulatory Cycle ◽  
Lh Surge ◽  
Syrian Hamsters ◽  
Reproductive Axis ◽  
Circadian Control ◽  
Double Label ◽  
Gonadotropin Inhibitory Hormone

Throughout most of the ovulatory cycle, estrogen negative feedback restrains the GnRH neuronal system. Just before ovulation, however, estrogen negative feedback is removed to permit stimulation of the preovulatory GnRH/LH surge (positive feedback) by the circadian clock in the suprachiasmatic nucleus (SCN). The mammalian ortholog of avian gonadotropin-inhibitory hormone, RFamide-related peptide 3 (RFRP-3), participates in the circadian-timed removal of estrogen negative feedback to permit the LH surge. The present study examined the specific neurochemical means by which the SCN controls RFRP-3 activity and explored whether the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to precisely time the LH surge. We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from SCN-derived vasopressin-ergic and vasoactive intestinal peptide (VIP)-ergic terminal fibers. Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas vasopressin was without effect at either time point. Double-label in situ hybridization for Rfrp-3 and the VIP receptors VPAC1 and VPAC2 revealed that the majority of RFRP-3 cells do not coexpress either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly. The timing of this VIP-mediated disinhibition is further coordinated via temporally gated responsiveness of RFRP-3 cells to circadian signaling. Together, these findings reveal a novel circadian hierarchy of control coordinating the preovulatory LH surge and ovulation.

scholarly journals RFamide-Related Peptide-3 Receptor Gene Expression in GnRH and Kisspeptin Neurons and GnRH-Dependent Mechanism of Action

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3770-3779 ◽  
Author(s):  
Mohammed Z. Rizwan ◽  
Matthew C. Poling ◽  
Maggie Corr ◽  
Pamela A. Cornes ◽  
Rachael A. Augustine ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Receptor Gene ◽  
Male Rats ◽  
Gonadotropin Secretion ◽  
Female Mice ◽  
Related Peptide ◽  
Gnrh Neurons ◽  
Lh Secretion ◽  
G Protein Coupled

RFamide-related peptide-3 (RFRP-3) is known to inhibit the activity of GnRH neurons. It is not yet clear whether its G protein-coupled receptors, GPR147 and GPR74, are present on GnRH neurons or on afferent inputs of the GnRH neuronal network or whether RFRP-3 can inhibit gonadotropin secretion independently of GnRH. We tested the following: 1) whether GnRH is essential for the effects of RFRP-3 on LH secretion; 2) whether RFRP-3 neurons project to GnRH and rostral periventricular kisspeptin neurons in mice, and 3) whether Gpr147 and Gpr74 are expressed by these neurons. Intravenous treatment with the GPR147 antagonist RF9 increased plasma LH concentration in castrated male rats but was unable to do so in the presence of the GnRH antagonist cetrorelix. Dual-label immunohistochemistry revealed that approximately 26% of GnRH neurons from male and diestrous female mice were apposed by RFRP-3 fibers, and 19% of kisspeptin neurons from proestrous female mice were apposed by RFRP-3 fibers. Using immunomagnetic purification of GnRH and kisspeptin cells, single-cell nested RT-PCR, and in situ hybridization, we showed that 33% of GnRH neurons and 9–16% of rostral periventricular kisspeptin neurons expressed Gpr147, whereas Gpr74 was not expressed in either population. These data reveal that RFRP-3 can act at two levels of the GnRH neuronal network (i.e. the GnRH neurons and the rostral periventricular kisspeptin neurons) to modulate reproduction but is unable to inhibit gonadotropin secretion independently of GnRH.

scholarly journals Rapid modulation of hypothalamic Kiss1 levels by the suckling stimulus in the lactating rat

2015 ◽  
Vol 227 (2) ◽  
pp. 105-115 ◽  
Author(s):  
Shimpei Higo ◽  
Satoko Aikawa ◽  
Norio Iijima ◽  
Hitoshi Ozawa
Keyword(s):  
Sensory Input ◽  
Arcuate Nucleus ◽  
Gnrh Secretion ◽  
Periventricular Nucleus ◽  
Neuronal Connections ◽  
Subsequent Exposure ◽  
Rapid Modulation ◽  
Anterograde Tracer ◽  
Lh Secretion

In mammals, lactation suppresses GnRH/LH secretion resulting in transient infertility. In rats, GnRH/LH secretion is rescued within 18–48 h after pup separation (PS) and rapidly re-suppressed by subsequent re-exposure of pups. To elucidate the mechanisms underlying these rapid modulations, changes in the expression of kisspeptin, a stimulator of GnRH secretion, in several lactating conditions (normal-lactating; 4-h PS; 18-h PS; 4-h PS +1-h re-exposure of pups; non-lactating) were examined usingin situhybridization. PS for 4 h or 18 h increasedKiss1expressing neurons in both the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), and subsequent exposure of pups re-suppressedKiss1in the AVPV. A change inKiss1expression was observed prior to the reported time of the change in GnRH/LH, indicating that the change in GnRH/LH results from changes in kisspeptin. We further examined the mechanisms underlying the rapid modulation ofKiss1. We first investigated the possible involvement of ascending sensory input during the suckling stimulus. Injection of the anterograde tracer to the subparafascicular parvocellular nucleus (SPFpc) in the midbrain, which relays the suckling stimulus, revealed direct neuronal connections between the SPFpc and kisspeptin neurons in both the AVPV and ARC. We also examined the possible involvement of prolactin (PRL). Administration of PRL for 1 h suppressedKiss1expression in the AVPV but not in the ARC. These results indicate that suckling stimulus rapidly modulatesKiss1expression directly via neuronal connections and indirectly through serum PRL, resulting in modulation in GnRH/LH secretion.

scholarly journals Kisspeptin Is Essential for the Full Preovulatory LH Surge and Stimulates GnRH Release from the Isolated Ovine Median Eminence

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1001-1012 ◽  
Author(s):  
Jeremy T. Smith ◽  
Qun Li ◽  
Kai Sing Yap ◽  
Muhammad Shahab ◽  
Antonia K. Roseweir ◽  
...  
Keyword(s):  
Median Eminence ◽  
Positive Feedback ◽  
Estradiol Benzoate ◽  
Portal System ◽  
Neuronal Tracing ◽  
Lh Surge ◽  
External Zone ◽  
Gnrh Secretion ◽  
Gnrh Neurons ◽  
Gnrh Release

Kisspeptins are the product of the Kiss1 gene and potently stimulate GnRH secretion. In sheep, Kiss1 mRNA-expressing cells are found in the arcuate nucleus (ARC) and dorsal-lateral preoptic area and both appear to mediate the positive feedback effect of estradiol to generate the preovulatory GnRH/LH surge. To determine the role of kisspeptin in transmitting estrogen-positive feedback in the hypothalamus, we administered the kisspeptin antagonist p-271 to ewes subjected to an estradiol benzoate-induced LH surge. Kisspeptin antagonist treatment significantly attenuated these LH surges. We further examined the response to kisspeptin treatment prior to the LH surge. Kisspeptin significantly stimulated GnRH secretion into the hypophysial portal system, but the response to kisspeptin was similar in luteal and late-follicular phase ewes. Kiss1r mRNA expression in GnRH neurons was also similar across the estrous cycle. To examine alternative pathways for kisspeptin stimulation of GnRH neurons, we examined the origin of kisspeptin neuronal fibers in the external zone of the median eminence (ME) using neuronal tracing and immunohistochemical techniques. ARC populations of kisspeptin neurons project fibers to the ME. Finally, we showed kisspeptin stimulates GnRH release from ovine ME-cultured explants. This suggests direct kisspeptin to GnRH terminal-to-terminal communication within the ME. Overall, these data indicate an essential role for kisspeptin in receiving stimulatory estrogen signals and generating the full positive feedback GnRH/LH surge. Kisspeptin neurons of the ARC project to the external zone of the ME and kisspeptin acts upon the GnRH fibers at this level.

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