Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Nov;156(11):4200-13.
doi: 10.1210/en.2015-1070. Epub 2015 Aug 24.

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

Cleyde V Helena  1 , Natalia Toporikova  1 , Bruna Kalil  1 , Andrea M Stathopoulos  1 , Veronika V Pogrebna  1 , Ruither O Carolino  1 , Janete A Anselmo-Franci  1 , Richard Bertram  1
Affiliations

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

Cleyde V Helena et al. Endocrinology. 2015 Nov.

Abstract

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Photomicrographs of coronal brain sections showing kisspeptin immunoreactivity in the arcuate region of rats submitted to microinjection of blank-SAP (A) or Nk3-SAP after 1, 2, or 3 weeks (B–D). Quantification of the number of kisspeptin cell bodies (E) and fiber density (F) in the arcuate region of the same animals. Data are shown as mean ± SEM. *, P < .05, **, P < .01, ***, P < .001 compared with control.
Figure 2.
Figure 2.
Photomicrographs of coronal brain sections showing kisspeptin, neurokinin B, and tyrosine hydroxylase immunoreactivity in the arcuate region of rats submitted to microinjection of blank-SAP (A, D, and G) or Nk3-SAP (B, E, and H) after 7–10 days. Quantification of the number of kisspeptin (C), neurokinin B (F), and tyrosine hydroxylase (I) cell bodies in the arcuate region of the same animals. Data are shown as mean ± SEM. **, P < .01, ***, P < .001 compared with control. Scale bar 100 μm.
Figure 3.
Figure 3.
Plasma LH levels (A) and kisspeptin content in the POA (B) and ME (C) from OVO rats submitted to microinjection of blank-SAP (n = 7) or Nk3-SAP (n = 7) into the arcuate nucleus. Blood samples were taken 7–10 days after neurotoxin injection, and brain punches were collected the following day at 4:00 pm. *, P < .05, **, P < .01 compared with blank-SAP.
Figure 4.
Figure 4.
Plasma LH levels (A) and kisspeptin content in the POA (B) and ME (C) from OVE rats submitted to microinjection of blank-SAP (n = 6) or Nk3-SAP (n = 7) into the ARC. Blood samples were taken 7–10 days after neurotoxin injection and brain punches were collected the following day at 4:00 pm. *, P < .05 compared with blank-SAP.
Figure 5.
Figure 5.
Plasma LH levels from OVE rats injected with saline (n = 10) or NOR-BNI (n = 7) into the AVPV. *, P < .05; ***, P < .001 (A). Arrows indicate time of the injection. Plasma LH levels from OVE rats injected with saline (n = 6) or dynorphin (n = 7) into the AVPV of KNDy-ablated rats. B, Photomicrograph of coronal brain section illustrating the microinjection placement in the AVPV (C).
Figure 6.
Figure 6.
Mathematical modeling simulation of the LH secretion in OVE rats including predictions generated by our simulations. A, Connections within the network model. Solid lines with pointed arrows represent stimulatory connections, whereas dashed lines with blunted arrows represents inhibitory connections. Model simulation results of KNDy neuron activity (B), AVPV kisspeptin neuron activity (C), and the LH level (D) with (solid lines) or without (dashed lines) ablation of KNDy neurons. SCN, suprachiasmatic nucleus.
See this image and copyright information in PMC

References

    1. Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145(9):4073–4077. - PubMed
    1. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun. 2004;320(2):383–388. - PubMed
    1. Smith JT, Saleh SN, Clarke IJ. Seasonal and cyclical change in the luteinizing hormone response to kisspeptin in the ewe. Neuroendocrinology. 2009;90(3):283–291. - PubMed
    1. Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA. 2005;102(6):2129–2134. - PMC - PubMed
    1. Dhillo WS, Murphy KG, Bloom SR. The neuroendocrine physiology of kisspeptin in the human. Rev Endocr Metab Disord. 2007;8(1):41–46. - PubMed

Publication types