scholarly journals Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4265-4275 ◽  
Author(s):  
V. M. Navarro ◽  
M. L. Gottsch ◽  
M. Wu ◽  
D. García-Galiano ◽  
S. J. Hobbs ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Male Mouse ◽  
Arcuate Nucleus ◽  
Feedback Regulation ◽  
Dynorphin A ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Gnrh Neurons ◽  
Kndy Neurons ◽  
Lh Secretion

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.

Development of gonadal feedback regulation of gonadotropin gene expression and secretion in female rats

1992 ◽  
Vol 127 (5) ◽  
pp. 454-458 ◽  
Author(s):  
Pirjo A Pakarinen ◽  
Ilpo T Huhtaniemi
Keyword(s):  
Negative Feedback ◽  
Feedback Regulation ◽  
Female Rats ◽  
Mrna Levels ◽  
Neonatal Rats ◽  
Adult Rats ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Pituitary Gonadotropin ◽  
Old Adult

The postnatal development of the gonadal negative feedback control of gonadotropins was studied in female rats. Neonatal (5-day-old) and randomly cycling young (60-day-old) and more mature (180-day-old) adult rats were ovariectomized, and half of them received Silastic implants containing the synthetic estrogen, diethylstilbestrol. The neonatal rats were killed 5, 10 or 15 days, and the adult rats 7 days after the operation. Age-matched and sham-operated animals served as controls. There were no statistically significant responses of serum LH or FSH concentrations or of the pituitary gonadotropin subunit mRNA levels to ovariectomy at any of the neonatal ages. A marked increase (p<0.01) after ovariectomy was seen in serum gonadotropins and in the cognate mRNA levels at both adult ages. In spite of the weak feedback response of the neonatal rats to ovariectomy, diethylstilbestrol suppressed the basal pituitary gonadotropin concentrations and the specific LH and FSH β-chain mRNAs (p<0.01–0.05). These results demonstrate that the gonadal negative feedback regulation of gonadotropin synthesis and secretion is not fully developed in neonatal and prepubertal female rats before 20 days of age. This is probably due to the steroidogenic quiescence of the ovaries in early life. However, the capability of the pituitary to respond to negative estrogen feedback has developed in the neonatal female, as demonstrated by the suppressive effects of diethylstilbestrol treatment on gonadotropin secretion.

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 Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 623-630 ◽  
Author(s):  
Jeremy T Smith ◽  
Donald K Clifton ◽  
Robert A Steiner
Keyword(s):  
Sex Steroids ◽  
Arcuate Nucleus ◽  
Direct Action ◽  
Hypogonadotropic Hypogonadism ◽  
Feedback Regulation ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Reproductive Axis ◽  
G Protein Coupled ◽  
The Brain

The Kiss1 gene codes for a family of peptides that act as endogenous ligands for the G protein-coupled receptor GPR54. Spontaneous mutations or targeted deletions of GPR54 in man and mice produce hypogonadotropic hypogonadism and infertility. Centrally administered kisspeptins stimulate gonadotropin secretion by acting directly on GnRH neurons. Sex steroids regulate the expression of KiSS-1 mRNA in the brain through direct action on KiSS-1 neurons. In the arcuate nucleus (Arc), sex steroids inhibit the expression of KiSS-1, suggesting that these neurons serve as a conduit for the negative feedback regulation of gonadotropin secretion. In the anteroventral periventricular nucleus (AVPV), sex steroids induce the expression of KiSS-1, implying that KiSS-1 neurons in this region may have a role in the preovulatory LH surge (in the female) or sexual behavior (in the male).

scholarly journals Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1546-1554 ◽  
Author(s):  
Sharon L. Dubois ◽  
Andrew Wolfe ◽  
Sally Radovick ◽  
Ulrich Boehm ◽  
Jon E. Levine
Keyword(s):  
Negative Feedback ◽  
Critical Role ◽  
Feedback Regulation ◽  
Mrna Levels ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Medial Basal Hypothalamus ◽  
Female Mice ◽  
Gnrh Release ◽  
17Β Estradiol

Abstract Elimination of estrogen receptorα (ERα) from kisspeptin (Kiss1) neurons results in premature LH release and pubertal onset, implicating these receptors in 17β-estradiol (E2)-mediated negative feedback regulation of GnRH release during the prepubertal period. Here, we tested the dependency of prepubertal negative feedback on ERα in Kiss1 neurons. Prepubertal (postnatal d 14) and peripubertal (postnatal d 34) wild-type (WT) and Kiss1 cell-specific ERα knockout (KERαKO) female mice were sham operated or ovariectomized and treated with either vehicle- or E2-containing capsules. Plasma and tissues were collected 2 days after surgery for analysis. Ovariectomy increased LH and FSH levels, and E2 treatments completely prevented these increases in WT mice of both ages. However, in prepubertal KERαKO mice, basal LH levels were elevated vs WT, and both LH and FSH levels were not further increased by ovariectomy or affected by E2 treatment. Similarly, Kiss1 mRNA levels in the medial basal hypothalamus, which includes the arcuate nucleus, were suppressed with E2 treatment in ovariectomized prepubertal WT mice but remained unaffected by any treatment in KERαKO mice. In peripubertal KERαKO mice, basal LH and FSH levels were not elevated vs WT and were unaffected by ovariectomy or E2. In contrast to our previous findings in adult animals, these results demonstrate that suppression of gonadotropins and Kiss1 mRNA by E2 in prepubertal animals depends upon ERα activation in Kiss1 neurons. Our observations are consistent with the hypothesis that these receptors play a critical role in restraining GnRH release before the onset and completion of puberty.

scholarly journals Seasonal changes in the negative feedback regulation of the secretion of the gonadotrophins by testosterone and inhibin in rams

1999 ◽  
Vol 160 (1) ◽  
pp. 155-167 ◽  
Author(s):  
AJ Tilbrook ◽  
DM de Kretser ◽  
IJ Clarke
Keyword(s):  
Breeding Season ◽  
Negative Feedback ◽  
Plasma Concentrations ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Blood Samples ◽  
Vehicle Treatment ◽  
Breeding Seasons ◽  
Lh Secretion ◽  
Hypothalamic Level

Three experiments were conducted with castrated Romney Marsh rams (wethers) to investigate the ability of testosterone and inhibin to suppress the secretion of LH and FSH during the breeding and the non-breeding seasons. In Experiment 1, wethers (n=5/group) were treated every 12 h for 7 days with oil or 16 mg testosterone propionate (i.m.) and were then given two i.v. injections either of vehicle or of 0.64 microg/kg human recombinant inhibin A (hr-inhibin) 6 h apart. Blood samples were collected for 4 h before inhibin or vehicle treatment and for 6 h afterwards for the assay of LH and FSH. In Experiments 2 and 3 wethers underwent hypothalamo-pituitary disconnection (HPD) and were given 125 ng GnRH i.v. every 2 h. In Experiment 2, HPD wethers (n=3/group) were injected (i.m.) every 12 h with oil or testosterone and blood samples were collected over 9 h before treatment and 7 days after treatment. In Experiment 3, HPD (n=5/group) wethers were treated with vehicle or hr-inhibin, as in Experiment 1, after treatment with oil, or 4, 8 or 16 mg testosterone twice daily for 7 days. Blood samples were collected over 4 h before treatment with vehicle or hr-inhibin and for 6 h afterwards. Treatment of wethers with testosterone (Experiment 1) resulted in a significant decrease in the plasma concentrations of LH and number of LH pulses per hour but the magnitude of these reductions did not differ between seasons. Testosterone treatment had no effect on LH secretion in GnRH-pulsed HPD wethers in either season and treatment with hr-inhibin did not affect LH secretion in wethers or HPD wethers in any instance. Plasma concentrations of FSH were significantly (P<0.05) reduced following treatment with testosterone alone during the breeding season but not during the non-breeding season. FSH levels were reduced to a greater extent by treatment with hr-inhibin but this effect was not influenced by season. During the non-breeding season, the effect of hr-inhibin to suppress FSH secretion was enhanced in the presence of testosterone. These experiments demonstrate that the negative feedback actions of testosterone on the secretion of LH in this breed of rams occurs at the hypothalamic level and is not influenced by season. In contrast, both testosterone and inhibin act on the pituitary gland to suppress the secretion of FSH and these responses are affected by season. Testosterone and inhibin synergize at the pituitary to regulate FSH secretion during the non-breeding season but not during the breeding season.

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