Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2016

Open Access 01-12-2016 | Research

Unilaterally blocking the muscarinic receptors in the suprachiasmatic nucleus in proestrus rats prevents pre-ovulatory LH secretion and ovulation

Authors: Elizabeth Vieyra, Deyra A. Ramírez, Noé Lagunas, Mario Cárdenas, Roberto Chavira, Pablo Damián-Matsumura, Angélica Trujillo, Roberto Domínguez, Leticia Morales-Ledesma

Published in: Reproductive Biology and Endocrinology | Issue 1/2016

Login to get access

Abstract

Background

The suprachiasmatic nucleus (SCN) and the cholinergic system of various regions of the hypothalamus participate in the regulation of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, which are necessary for the occurrence of ovulation. In the present study, our goal was to analyse the effects of unilaterally blocking the muscarinic receptors in the SCN on ovulation and steroid secretion.

Methods

Cyclic rats were randomly allotted to one of the experimental groups. Groups of 8–14 rats were anaesthetized and microinjected with 0.3 μl of saline or a solution of atropine (62.5 ng in 0.3 μl of saline) into the left or right SCN at 09.00 or 19.00 h during diestrus-1 or on the proestrus day. The rats were euthanized on the predicted day of oestrus, and evaluated ovulation and levels of progesterone and oestradiol. Other groups of 10 rats were microinjected with atropine into the left or right SCNs at 09.00 h on the proestrus day, were euthanized eight h later, and luteinizing hormone (LH) was measured.

Results

At 09.00 or 19.00 h during diestrus-1, atropine microinjections into the SCNs on either side did not modify ovulation. The atropine microinjections performed at 09.00 h of proestrus into either side of the SCN blocked ovulation (right SCN: 1/9 ovulated vs. 9/10 in the saline group; left SCN: 8/14 ovulated vs. 10/10 in the saline group). The LH levels at 17.00 h in the rats that were microinjected with atropine at 09.00 h of proestrus were lower than those of the controls. In the non-ovulating atropine-treated rats, the injection of synthetic LH-releasing hormone (LHRH) restored ovulation. Atropine treatment at 19.00 h of proestrus on either side of the SCN did not modify ovulation, while the progesterone and oestradiol levels were lower.

Conclusion

Based on the present results, we suggest that the cholinergic neural information arriving on either side of the SCN is necessary for the pre-ovulatory secretion of LH to induce ovulation. Additionally, the regulation of progesterone and oestradiol secretion by the cholinergic innervation of the SCN varies with the time of day, the day of the cycle, and the affected SCN.
Literature
1.
Urlep Z, Rozman D. The interplay between circadian system, cholesterol synthesis, and steroidogenesis affects various aspects of female reproduction. Front Endocrino (Lausanne). 2013;4:11.
2.
Brown-Grant K, Raisman G. Abnormalities in reproductive function associated with the destruction of the suprachiasmatic nuclei in female rats. Proc R Soc Lond B Biol Sci. 1977;198(1132):279–96.CrossRefPubMed
3.
Samson WK, McCann SM. Effects of suprachiasmatic nucleus lesions on the hypothalamic LH-releasing hormone (LHRH) content and gonadotropin secretion in the ovariectomized (OVX) female rat. Brain Res Bull. 1979;4(6):783–8.CrossRefPubMed
4.
Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology. 1982;34(6):395–404.CrossRefPubMed
5.
Ma YJ, Kelly MJ, Rönnekleiv OK. Pro-gonadotropin-releasing hormone (ProGnRH) and GnRH content in the preoptic area and the basal hypothalamus of anterior medial preoptic nucleus/suprachiasmatic nucleus-lesioned persistent estrous rats. Endocrinology. 1990;127(6):2654–64.CrossRefPubMed
6.
Ojeda SR, Lomniczi A, Mastronardi C, Heger S, Roth C, Paret AS, Matagne V, Mungenast AE. Minireview: the neuroendocrine regulation of puberty: is time ripe for a systems biology approach? Endocrinology. 2006;147(3):1166–74.CrossRefPubMed
7.
Dungan HM, Gottsch ML, Zeng H, Gragerov A, Bergmann JE, Vassilatis DK, Clifton DK, Steiner RA. The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J Neurosci. 2007;27(44):12088–95.CrossRefPubMed
8.
Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008;28(35):8691–7.CrossRefPubMed
9.
Clarkson J, Herbison AE. Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. J Neuroendocrinol. 2009;21(4):305–11.CrossRefPubMed
10.
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92(3):1235–316.CrossRefPubMed
11.
12.
Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS. Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. Endocrinology. 2009;150(8):3664–71.CrossRefPubMedPubMedCentral
13.
Van der Beek EM, Wiegant VM, van der Donk HA, van den Hurk R, Buijs RM. Lesions of the suprachiasmatic nucleus indicate the presence of a direct vasoactive intestinal polypeptide-containing projection to gonadotrophin-releasing hormone neurons in the female rat. J Neuroendocrinol. 1993;5(2):137–44.CrossRefPubMed
14.
Tonsfeldt KJ, Chappell PE. Clocks on top: the role of the circadian clock in the hypothalamic and pituitary regulation of endocrine physiology. Mol Cell Endocrinol. 2012;349(1):3–12.CrossRefPubMed
15.
Vida B, Deli L, Hrabovszky E, Kalamatianos T, Caraty A, Coen CW, Liposits Z, Kalló I. Evidence for suprachiasmatic vasopressin neurones innervating kisspeptin neurones in the rostral periventricular area of the mouse brain: regulation by oestrogen. J Neuroendocrinol. 2010;22(9):1032–9.CrossRefPubMed
16.
Colledge WH. Kisspeptins and GnRH neuronal signalling. Trends Endocrinol Metab. 2009;20(3):115–21.CrossRefPubMed
17.
Bina KG, Rusak B, Semba K. Localization of cholinergic neurons in the forebrain and brainstem that project to the suprachiasmatic nucleus of the hypothalamus in rat. J Comp Neurol. 1993;335(2):295–307.CrossRefPubMed
18.
Yang JJ, Wang YT, Cheng PC, Kuo YJ, Huang RC. Cholinergic modulation of neuronal excitability in the rat suprachiasmatic nucleus. J Neurophysiol. 2010;103(3):1397–409.CrossRefPubMed
19.
Madeira MD, Pereira PA, Silva SM, Cadete-Leite A, Paula-Barbosa MM. Basal forebrain neurons modulate the synthesis and expression of neuropeptides in the rat suprachiasmatic nucleus. Neuroscience. 2004;125(4):889–901.CrossRefPubMed
20.
Hut RA, Van der Zee EA. The cholinergic system, circadian rhythmicity, and time memory. Behav Brain Res. 2011;221(2):466–80.CrossRefPubMed
21.
Silverman AJ, Livne I, Witkin JW. The gonadotrophin-releasing hormone (GnRH), neuronal systems: Immunocytochemistry and in situ hybridization. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction. New York: Raven; 1994. p. 1683–706.
22.
Turi GF, Liposits Z, Hrabovszky E. Cholinergic afferents to gonadotropin-releasing hormone neurons of the rat. Neurochem Int. 2008;52(4–5):723–8.CrossRefPubMed
23.
Everett JW, Sawyer CH, Markee JE. A neurogenic timing factor in control of the ovulatory discharge of luteinizing hormone in the cyclic rat. Endocrinology. 1949;44(3):234–50.CrossRefPubMed
24.
Cruz ME, Jaramillo LP, Domínguez R. Asymmetric ovulatory response induced by a unilateral implant of atropine in the anterior hypothalamus in the cyclic rat. J Endocrinol. 1989;123(3):437–9.CrossRefPubMed
25.
Cruz ME, Castro J, Domínguez R. A comparative analysis of the neuroendocrine mechanisms regulating ovulation, affected by a unilateral implant of atropine in the preoptic-anterior hypothalamic area, in intact and hemiovariectomized adult rats. J Endocrinol. 1992;133(2):205–10.CrossRefPubMed
26.
Flores A, Meléndez G, Palafox MT, Rodríguez JO, Barco AI, Chavira R, Domínguez R, Cruz ME. The participation of the cholinergic system in regulating progesterone secretion through the ovarian-adrenal crosstalk varies along the estrous cycle. Endocrine. 2005;28(2):145–51.CrossRefPubMed
27.
Cruz ME, Flores A, Palafox MT, Meléndez G, Rodríguez OJ, Chavira R, Domínguez R. The role of the muscarinic system in regulating estradiol secretion varies during the estrous cycle: the hemiovariectomized rat model. Reprod Biol Endocrinol. 2006;4:43.CrossRefPubMedPubMedCentral
28.
Bock GR, Marsh J. Biological asymmetry and handedness. In: “CIBA Foundation symposium 162”, Toronto. Chichester/New York/Brisbane/Singapore: Wiley; 1991.
29.
Michel S, Marek R, vanderleest HT, vansteensel MJ, Schwartz WJ, Colwell CS, Meijer JH. Mechanism of bilateral communication in the suprachiasmatic nucleus. Eur J Neurosci. 2013;37(6):964–71.CrossRefPubMed
30.
Pickard GE, Turek FW. Splitting of the circadian rhythm of activity is abolished by unilateral lesions of the suprachiasmatic nuclei. Science. 1982;215(4536):1119–21.CrossRefPubMed
31.
Zhang L, Aguilar-Roblero R. Asymmetrical electrical activity between the suprachiasmatic nuclei in vitro. Neuroreport. 1995;6(3):537–40.CrossRefPubMed
32.
Domínguez R, Riboni L, Zipitría D, Revilla R. Is there a cholinergic circadian rhythm throughout the oestrous cycle related to ovulation in the rat? J Endocrinol. 1982;95(2):175–80.CrossRefPubMed
33.
34.
Goodchild CS, Serrao JM, Kolosov A, Boyd BJ. Alphaxalone reformulated: a water-soluble intravenous anesthetic preparation in sulfobutyl-ether-β cyclodextrin. Anesth Analg. 2015;120(5):1025–31.CrossRefPubMed
35.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed. London: Elsevier Academic; 2004.
36.
Lohman RJ, Liu L, Morris M, O’Brien TJ. Validation of a method for localised microinjection of drugs into thalamic subregions in rats for epilepsy pharmacological studies. J Neurosci Methods. 2005;146(2):191–7.CrossRefPubMed
37.
Humphrey RR, Dermody WC, Brink HO, Bousley FG, Schottin NH, Sakowski R, Vaitkus JW, Veloso HT, Reel JR. Induction of luteinizing hormone (LH) release and ovulation in rats, hamsters, and rabbits by synthetic luteinizing hormone-releasing factor (LRF). Endocrinology. 1973;92(5):1515–26.CrossRefPubMed
38.
39.
Dhibi S, Ettaya A, Elfeki A, Hfaiedh N. Protective effects of Artemisia arborescens essential oil on oestroprogestative treatment induced hepatotoxicity. Nutr Res Pract. 2015;9(5):466–71.CrossRefPubMedPubMedCentral
40.
Funabashi T, Jinnai K, Sano A, Shinohara K, Kimura F. Pentobarbital stimulates the activity of the GnRH pulse generator interacting with opioid neurons in rats in proestrus. Psychoneuroendocrinology. 2000;25:277–87.CrossRefPubMed
41.
Domínguez R, Smith ER. Barbiturate blockade of ovulation on days other than proestrus in the rat. Neuroendocrinology. 1974;14(3):212–23.PubMed
42.
Weick RF, Smith ER, Domínguez R, Dhariwal AP, Davidson JM. Mechanism of stimulatory feedback effect of estradiol benzoate on the pituitary. Endocrinology. 1971;88(2):293–301.CrossRefPubMed
43.
Everett JW. “Pituitary and hypothalamus: perspectives and overview”. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction. St. Louis: Elsevier Press; 2006. p. 1289–308.CrossRef
44.
Abbott SM, Arnold JM, Chang Q, Miao H, Ota N, Cecala C, Gold PE, Sweedler JV, Gillette MU. Signals from the brainstem sleep/wake centers regulate behavioral timing via the circadian clock. PLoS One. 2013;8(8):e70481.CrossRefPubMedPubMedCentral
45.
Palm IF, Van Der Beek EM, Wiegant VM, Buijs RM, Kalsbeek A. Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesions of the suprachiasmatic nucleus. Neuroscience. 1999;93(2):659–66.CrossRefPubMed
46.
Loh DH, Kuljis DA, Azuma L, Wu Y, Truong D, Wang HB, Colwell CS. Disrupted reproduction, estrous cycle, and circadian rhythms in female mice deficient in vasoactive intestinal peptide. J Biol Rhythms. 2014;29(5):355–69.CrossRefPubMedPubMedCentral
47.
Cruz ME, Flores A, Domínguez R. The cholinergic system of the preoptic-anterior hypothalamic areas regulates the ovarian follicular population in an asymmetric way. Endocrine. 2014;47(3):913–22.CrossRefPubMed
48.
Cruz ME, Flores A, Alvarado BE, Hernández CG, Zárate A, Chavira R, Cárdenas M, Arrieta-Cruz I, Gutiérrez-Juárez R. Ovulation requires the activation on proestrus of M1 muscarinic receptors in the left ovary. Endocrine. 2015;49(3):809–19.CrossRefPubMed
49.
Espey LL, Richards JS. Ovulation. In: Neil JD, editors. Physiology of Reproduction. Amsterdam: Academic Press; 2006. p. 425–74.
50.
Crespo D, Goetz FW, Planas JV. Luteinizing hormone induces ovulation via tumor necrosis factor α-dependent increases in prostaglandin F2α in a nonmammalian vertebrate. Sci Rep. 2015;5:14210.CrossRefPubMedPubMedCentral
51.
Liu C, Gillette MU. Cholinergic regulation of the suprachiasmatic nucleus circadian rhythm via a muscarinic mechanism at night. J Neurosci. 1996;16(2):744–51.PubMed
52.
Cruz ME, Villegas G, Domínguez-González A, Chavira R, Domínguez R. Ovulation delay induced by blockade of the cholinergic system on dioestrus-1, is related to changes in dopaminergic activity of the preoptic anterior-hypothalamic area of the rat. Brain Res Bull. 2001;54(4):339–44.CrossRefPubMed
53.
Smarr BL, Morris E, de la Iglesia HO. The dorsomedial suprachiasmatic nucleus times circadian expression of Kiss1 and the luteinizing hormone surge. Endocrinology. 2012;153(6):2839–50.CrossRefPubMedPubMedCentral
54.
d’Anglemont de Tassigny X, Fagg LA, Carlton MB, Colledge WH. Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology. 2008;149(8):3926–32.CrossRef
55.
Gerendai I, Halász B. Asymmetry of the neuroendocrine system. News Physiol Sci. 2001;16:92–5.PubMed
56.
Sánchez MA, López-García JC, Cruz ME, Tapi R, Domínguez R. Asymmetrical changes in the choline acetyltransferase activity in the preoptic-anterior hypothalamic area during the oestrous cycle of the rat. Neuroreport. 1994;5(4):433–4.CrossRefPubMed
57.
Yan L, Okamura H. Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus. Eur J Neurosci. 2002;15(7):1153–62.CrossRefPubMed
58.
59.
60.
Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci. 1999;11(5):1535–44.CrossRefPubMed
61.
Chung S, Son GH, Kim K. Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta. 2011;1812(5):581–91.CrossRefPubMed
62.
Kornya L, Bódis J, Koppán M, Tinneberg HR, Török A. Modulatory effect of acetylcholine on gonadotropin-stimulated human granulosa cell steroid secretion. Gynecol Obstet Invest. 2001;52(2):104–7.CrossRefPubMed
Metadata
Title
Unilaterally blocking the muscarinic receptors in the suprachiasmatic nucleus in proestrus rats prevents pre-ovulatory LH secretion and ovulation
Authors
Elizabeth Vieyra
Deyra A. Ramírez
Noé Lagunas
Mario Cárdenas
Roberto Chavira
Pablo Damián-Matsumura
Angélica Trujillo
Roberto Domínguez
Leticia Morales-Ledesma
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2016
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-016-0168-7

Other articles of this Issue 1/2016

Reproductive Biology and Endocrinology 1/2016 Go to the issue

Methodology

Assessment of clinical application of preimplantation genetic screening on cryopreserved human blastocysts

Erratum

Erratum: Biosimilar FSH preparations- are they identical twins or just siblings?

Research

Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea?

Research

Divergent activity of the gonadotropin-releasing hormone receptor gene promoter among genetic lines of pigs is partially conferred by nuclear factor (NF)-kB, specificity protein (SP)1-like and GATA-4 binding sites

Research

Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation

Research

Selecting the embryo with the highest implantation potential using a data mining based prediction model