Neurons that synthesize and secrete gonadotropin-releasing hormone (GnRH) represent the neural control point for fertility modulation in vertebrates. As such GnRH neurons are ideally situated to integrate stress responses on reproduction. By isolating individual GnRH neurons from acute brain slices of adult female GnRH-EGFP transgenic mice and using microarray analyses, we have identified a range of transcripts encoding receptors known to be involved in stress responses in GnRH neurons. Prominent among these were receptors for corticotropin-releasing hormone (CRH), vasopressin, interleukins, prostaglandins, tumor necrosis factor alpha and other inflammatory mediators. We selected 4 of these targets [interleukin 1 receptor accessory protein (IL-1Racc), prostaglandin E2 receptor subtype EP2 (PGER2), CRH receptor type 1 (CRH-R1), and arginine-vasopressin receptor type 1b (AVP-R1b)] for validation using single-cell RT-PCR from individual GnRH neurons. In total, 54% of GnRH neurons (n = 26) were found to express at least 1 of these transcripts. The IL-1Racc, PGER2 and CRH-R1 mRNAs were each detected in approximately 25% of the GnRH neurons tested, but no evidence was found for AVP-R1b transcripts. Overlap was found between the expression of CRH-R1 and PGER2, and IL-1Racc and PGER2 in individual GnRH neurons. Dual immunofluorescence experiments confirmed the expression of CRH-R1/2 in a subpopulation (∼30%) of GnRH neurons. These observations indicate that a variety of different stressors and stress pathways have the capacity to have an impact directly upon a subpopulation of GnRH neurons to influence the reproductive axis.

Keywords:
Gonadotropin-releasing hormone neurons, Corticotropin, Molecular neuroendocrinology, Mice
1.
Wingfield JC, Sapolsky RM: Reproduction and resistance to stress: when and how. J Neuroendocrinol 2003;15:711–724.
2.
Dobson H, Ghuman S, Prabhakar S, Smith R: A conceptual model of the influence of stress on female reproduction. Reproduction 2003;125:151–163.
3.
Sawchenko PE, Brown ER, Chan RK, Ericsson A, Li HY, Roland BL, Kovacs KJ: The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 1996;107:201–222.
4.
Sawchenko PE, Li HY, Ericsson A: Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res 2000;122:61–78.
5.
Dayas CV, Buller KM, Crane JW, Xu Y, Day TA: Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 2001;14:1143–1152.
6.
Ericsson A, Kovacs KJ, Sawchenko PE: A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J Neurosci 1994;14:897–913.
7.
Li HY, Sawchenko PE: Hypothalamic effector neurons and extended circuitries activated in ‘neurogenic’ stress: a comparison of footshock effects exerted acutely, chronically and in animals with controlled glucocorticoid levels. J Comp Neurol 1998;393:244–266.
8.
Reyes TM, Walker JR, DeCino C, Hogenesch JB, Sawchenko PE: Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J Neurosci 2003;23:5607–5616.
9.
Rivest S, Plotsky PM, Rivier C: CRF alters the infundibular LHRH secretory system from the medial preoptic area of female rats: possible involvement of opioid receptors. Neuroendocrinology 1993;57:236–246.
10.
Rivest S, Rivier C: The role of corticotropin-releasing factor and interleukin-1 in the regulation of neurons controlling reproductive functions. Endocr Rev 1995;16:177–199.
11.
Cates PS, Forsling ML, O’Byrne KT: Stress-induced suppression of pulsatile luteinising hormone release in the female rat: the role of vasopressin. J Neuroendocrinol 1999;11:677–683.
12.
Li XF, Bowe JE, Lightman SL, O’Byrne KT: Role of corticotropin-releasing factor receptor-2 in stress-induced suppression of pulsatile luteinizing hormone secretion in the rat. Endocrinology 2005;146:318–322.
13.
MacLusky NJ, Naftolin F, Leranth C: Immunocytochemical evidence for direct synaptic connections between corticotrophin-releasing factor (CRF) and gonadotrophin-releasing hormone (GnRH)-containing neurons in the preoptic area of the rat. Brain Res 1988;439:391–395.
14.
Ahima RS, Harlan RE: Glucocorticoid receptors in LHRH neurons. Neuroendocrinology 1992;56:845–850.
15.
Han SK, Todman MG, Herbison AE: Endogenous GABA release inhibits the firing of adult gonadotropin-releasing hormone neurons. Endocrinology 2004;145:495–499.
16.
Todman MG, Han SK, Herbison AE: Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays. Neuroscience 2005;132:703–712.
17.
Skynner MJ, Sim JA, Herbison AE: Detection of estrogen receptor alpha and beta messenger ribonucleic acids in adult gonadotropin-releasing hormone neurons. Endocrinology 1999;140:5195–5201.
18.
Campbell RE, Han SK, Herbison AE: Biocytin filling of adult gonadotropin-releasing hormone neurons in situ reveals extensive, spiny, dendritic processes. Endocrinology 2005;146:1163–1169.
19.
Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates. San Diego, Academic Press, 2004.
20.
Chen Y, Brunson KL, Muller MB, Cariaga W, Baram TZ: Immunocytochemical distribution of corticotropin-releasing hormone receptor type 1 [CRF(1)]-like immunoreactivity in the mouse brain: light microscopy analysis using an antibody directed against the C terminus. J Comp Neurol 2000;420:305–323.
21.
Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K: The IL-1 receptor accessory protein is responsible for the recruitment of the interleukin-1 receptor-associated kinase to the IL-1/IL-1 receptor I complex. FEBS Lett 1997;419:41–44.
22.
Herbison AE: Physiology of the GnRH neuronal network; in Neill JD (ed): Knobil and Neill’s Physiology of Reproduction. San Diego, Academic Press, 2006, pp 1415–1482.
23.
Hurbin A, Boissin-Agasse L, Orcel H, Rabie A, Joux N, Desarmenien MG, Richard P, Moos FC: The V1a and V1b, but not V2, vasopressin receptor genes are expressed in the supraoptic nucleus of the rat hypothalamus, and the transcripts are essentially colocalized in the vasopressinergic magnocellular neurons. Endocrinology 1998;139:4701–4707.
24.
Hahn JD, Kalamatianos T, Coen CW: Studies on the neuroanatomical basis for stress-induced oestrogen-potentiated suppression of reproductive function: evidence against direct corticotropin-releasing hormone projections to the vicinity of luteinizing hormone-releasing hormone cell bodies in female rats. J Neuroendocrinol 2003;15:732–742.
25.
Mitchell JC, Li XF, Breen L, Thalabard JC, O’Byrne KT: The role of the locus coeruleus in corticotropin-releasing hormone and stress-induced suppression of pulsatile luteinizing hormone secretion in the female rat. Endocrinology 2005;146:323–331.
26.
Dudas B, Merchenthaler I: Close anatomical associations between beta-endorphin and luteinizing hormone-releasing hormone neuronal systems in the human diencephalon. Neuroscience 2004;124:221–229.
27.
Ericsson A, Arias C, Sawchenko PE: Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 1997;17:7166–7179.
28.
Ojeda SR, Negro-Vilar A, McCann SM: Evidence for involvement of α-adrenergic receptors in norepinephrine-induced prostaglandin E2 and luteinizing hormone-releasing hormone release from the median eminence. Endocrinology 1982;110:409–411.
29.
Rage F, Lee BJ, Ma YJ, Ojeda SR: Estradiol enhances prostaglandin E2 receptor gene expression in luteinizing hormone-releasing hormone (LHRH) neurons and facilitates the LHRH response to PGE2 by activating a glia-to-neuron signaling pathway. J Neurosci 1997;17:9145–9156.
30.
De Smet F, Moreau Y, Engelen K, Timmerman D, Vergote I, De Moor B: Balancing false positives and false negatives for the detection of differential expression in malignancies. Br J Cancer 2004;91:1160–1165.
31.
Thind KK, Boggan JE, Goldsmith PC: Interactions between vasopressin- and gonadotropin-releasing hormone-containing neuroendocrine neurons in the monkey supraoptic nucleus. Neuroendocrinology 1991;53:287–297.
© 2005 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.