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      Expression of mRNAs Encoding Receptors That Mediate Stress Signals in Gonadotropin-Releasing Hormone Neurons of the Mouse

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          Abstract

          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 E<sub>2</sub> 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.

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          Most cited references 21

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          Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups.

          It has been hypothesized that the brain categorizes stressors and utilizes neural response pathways that vary in accordance with the assigned category. If this is true, stressors should elicit patterns of neuronal activation within the brain that are category-specific. Data from previous immediate-early gene expression mapping studies have hinted that this is the case, but interstudy differences in methodology render conclusions tenuous. In the present study, immunolabelling for the expression of c-fos was used as a marker of neuronal activity elicited in the rat brain by haemorrhage, immune challenge, noise, restraint and forced swim. All stressors elicited c-fos expression in 25-30% of hypothalamic paraventricular nucleus corticotrophin-releasing-factor cells, suggesting that these stimuli were of comparable strength, at least with regard to their ability to activate the hypothalamic-pituitary-adrenal axis. In the amygdala, haemorrhage and immune challenge both elicited c-fos expression in a large number of neurons in the central nucleus of the amygdala, whereas noise, restraint and forced swim primarily elicited recruitment of cells within the medial nucleus of the amygdala. In the medulla, all stressors recruited similar numbers of noradrenergic (A1 and A2) and adrenergic (C1 and C2) cells. However, haemorrhage and immune challenge elicited c-fos expression in subpopulations of A1 and A2 noradrenergic cells that were significantly more rostral than those recruited by noise, restraint or forced swim. The present data support the suggestion that the brain recognizes at least two major categories of stressor, which we have referred to as 'physical' and 'psychological'. Moreover, the present data suggest that the neural activation footprint that is left in the brain by stressors can be used to determine the category to which they have been assigned by the brain.
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            Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays.

            The definition of neurotransmitter receptors expressed by individual neuronal phenotypes is essential for our understanding of integrated neural regulation. We report here a single-neuron strategy using green fluorescent protein (GFP)-promoter transgenic mice and oligonucleotide microarrays that has enabled us to provide a qualitative profile of the neurotransmitter receptors expressed by the gonadotropin- releasing hormone (GnRH) neurons, critical for the neural regulation of fertility. Acute brain slices were prepared from adult female GnRH-GFP transgenic mice and single GnRH neurons identified and patched. The contents of GnRH neurons underwent reverse transcription and cDNA amplification using the switch mechanism at the 5' end of RNA templates system, and hybridization to mouse gene oligonucleotide arrays. Fifty different neurotransmitter receptor subunit mRNAs were detected in GnRH neurons. Many of the classical amino acid and aminergic receptors were present in addition to 14 distinct, and in most cases novel, neuropeptidergic receptor signaling families. Four of the latter were selected for functional validation with gramicidin-perforated patch-clamp electrophysiology. Galanin, GnRH and neuromedin B were all found to exert direct depolarizing actions upon GnRH neurons whereas somatostatin induced a potent hyperpolarizing response. These studies demonstrate a relatively straightforward approach for transcriptome profiling of specific neuronal phenotypes. The stimulatory actions of GnRH and galanin upon GnRH neurons found here indicate that positive ultrashort feedback loops exist among the GnRH neuronal population.
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              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.

              Corticotropin-releasing hormone (CRH) receptor type 1 (CRF(1)) is a member of the receptor family mediating the effects of CRH, a critical neuromediator of stress-related endocrine, autonomic, and behavioral responses. The detailed organization and fine localization of CRF(1)-like immunoreactivity (CRF(1)-LI) containing neurons in the rodent have not been described, and is important to better define the functions of this receptor. Here we characterize in detail the neuroanatomical distribution of CRF(1)-immunoreactive (CRF(1)-ir) neurons in the mouse brain, using an antiserum directed against the C-terminus of the receptor. We show that CRF(1)-LI is abundantly yet selectively expressed, and its localization generally overlaps the target regions of CRH-expressing projections and the established distribution of CRF(1) mRNA, with several intriguing exceptions. The most intensely CRF(1)-LI-labeled neurons are found in discrete neuronal systems, i.e., hypothalamic nuclei (paraventricular, supraoptic, and arcuate), major cholinergic and monoaminergic cell groups, and specific sensory relay and association thalamic nuclei. Pyramidal neurons in neocortex and magnocellular cells in basal amygdaloid nucleus are also intensely CRF(1)-ir. Finally, intense CRF(1)-LI is evident in brainstem auditory associated nuclei and several cranial nerves nuclei, as well as in cerebellar Purkinje cells. In addition to their regional specificity, CRF(1)-LI-labeled neurons are characterized by discrete patterns of the intracellular distribution of the immunoreaction product. While generally membrane associated, CRF(1)-LI may be classified as granular, punctate, or homogenous deposits, consistent with differential membrane localization. The selective distribution and morphological diversity of CRF(1)-ir neurons suggest that CRF(1) may mediate distinct functions in different regions of the mouse brain. Copyright 2000 Wiley-Liss, Inc.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2005
                May 2006
                31 May 2006
                : 82
                : 5-6
                : 320-328
                Affiliations
                Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin, New Zealand
                Article
                93155 Neuroendocrinology 2005;82:320–328
                10.1159/000093155
                16721036
                © 2005 S. Karger AG, Basel

                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.

                Page count
                Figures: 2, Tables: 3, References: 31, Pages: 9
                Categories
                Original Paper

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