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Departments of Physiology (Y.O., J.S., K.K., Y.U.) and Urology (T.M.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan; Department of Physiology (T.O.), Jichi Medical School, Tochigi 329-0498, Japan; and Department of Third Internal Medicine (M.N.), Miyazaki Medical College, Miyazaki 889-1692, Japan
Address all correspondence and requests for reprints to: Yoichi Ueta, M.D., Ph.D., Department of Physiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail: yoichi{at}med.uoeh-u.ac.jp.
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Introduction |
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Recent studies have demonstrated that NMU is an endogenous ligand of G protein-coupled orphan receptors, NMU1R and NMU2R (previously called as FM-3 and FM-4, respectively) (8, 10, 11, 12). NMU1R is expressed abundantly in the small intestine with little expression in the rat brain (8, 10, 11, 12). The expression of NMU2R is mostly restricted to specific regions in the rat brain, in particular the hypothalamic paraventricular nucleus (PVN), the wall of the third ventricle in the hypothalamus, and the CA1 region of the hippocampus (8).
The PVN, as well as the supraoptic nucleus (SON), is known to synthesize arginine vasopressin (AVP) and oxytocin (OXT), which are released into general circulation through terminal axons located in the posterior pituitary. The parvocellular division of the PVN synthesizes CRH, which stimulates the secretion of ACTH in the anterior pituitary.
The abundant expression of the NMU2R gene in the rat PVN raised the possibility that central NMU may be involved in the regulation of the secretion of AVP, OXT, and CRH-induced secretion of ACTH. However, there is no evidence to suggest that central NMU may modulate the release of AVP, OXT, and CRH-induced secretion of ACTH. Thus, in the present study, we examined that the effects of intracerebroventricular (icv) administration of NMU on plasma concentrations of AVP, OXT, and ACTH in rats, using RIA. We also examined the effects of icv administration of NMU on the induction of the c-fos protein (Fos) and the expression of the c-fos gene in the PVN and SON, using immunohistochemistry for Fos and in situ hybridization histochemistry for the c-fos mRNA. The specificity of the effects of icv administration of NMU on neurosecretion and the expression of the c-fos gene in the PVN and SON were confirmed by pretreatment with anti-NMU IgG. In addition, dual immunostaining for Fos/AVP and Fos/OXT was performed to determine whether icv administration of NMU activates these cells selectively. The expression of the c-fos gene has been widely used to detect the neuronal activity in the CNS (13).
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Materials and Methods |
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Surgical procedures
For icv administration of NMU or saline, the animals were anesthetized (sodium pentobarbital, 50 mg/kg body weight, ip injection) and then placed in a stereotaxic frame. A stainless steel guide cannula (550-µm outer diameter, 10.5-mm length) was implanted stereotaxically, following coordinates given by Paxinos and Watson (14). These coordinates were 0.8 mm posterior to the bregma, 1.4 mm lateral to midline, and 2.0 mm below the surface of the left cortex such that a tip of the cannula was 1.5 mm above the left cerebral ventricle. Two stainless steel anchoring screws were fixed to the skull, and the cannula was secured in place by acrylic dental cement. The animals were then returned to their cages and allowed to recover for at least 7 d. The animals were then handled every day and housed in cages before the start of the experiments.
Central administration of NMU, anti-NMU IgG, and saline
For icv administration of NMU, anti-NMU IgG, and saline, a stainless steel injector (300 µm, outer diameter) was introduced through the cannula at a depth of 1.5 mm beyond the end of the guide. The total volume of injected solution of NMU and saline into the lateral ventricle was 7.9 µl, which was then dissolved in a sterile 0.9% saline solution. Rat NMU was purchased from the Peptide Institute (Minoh, Japan). Control serum IgG (1 µg/5 µl) or anti-NMU IgG (1 µg/5 µl) were icv administered just before icv administration of NMU (1 nmol, 2.64 µl). The specificity of anti-NMU IgG were previously described (12).
Experimental procedures
In the first experiment, NMU (3 nmol/rat) or saline was administered icv (n = 5–12 in each group). The animals were decapitated 5, 15, 30, 60, or 180 min after icv administration. Brains were removed and placed on powdered dry ice for in situ hybridization histochemistry for the c-fos gene. The trunk blood was collected for measuring plasma concentrations of AVP, OXT, ACTH, and corticosterone, using RIA.
In the second experiment, icv administration of NMU (0.1, 1, and 3 nmol/rat) or saline was also performed (n = 6–8 in each group). The animals were decapitated 15 min after administration of the solution. The trunk blood was collected for measuring plasma AVP, OXT, and ACTH, using RIA.
In the third experiment, NMU (1 nmol/rat), control serum IgG (1 µg/rat) + NMU (1 nmol/rat), and anti-NMU IgG (1 µg/rat) + NMU (1 nmol/rat) or saline were centrally administered (n = 6–8 in each group). The animals were decapitated 30 min after icv administration. Brains were removed and placed on powdered dry ice for in situ hybridization histochemistry for the c-fos gene. The trunk blood was collected for measuring plasma concentrations of OXT and ACTH and corticosterone, using RIA.
In the final experiment, NMU (3 nmol/rat) or saline was administered icv (n = 3 in each group). Ninety minutes after icv administration of the solution, the animals were anesthetized deeply with an ip injection of sodium pentobarbital (75 mg/kg body weight) following perfusion and then the fixed brains were used for immunohistochemistry for Fos, AVP, and OXT.
All experimental procedures in this study were performed in accordance with the guidelines set by the use and care of laboratory animals by the Physiological Society of Japan and approved by the animal care committee at this institution.
RIA for AVP, OXT, ACTH, and corticosterone
Plasma concentrations of AVP and OXT were determined by RIA with specific anti-AVP (15) and anti-OXT (16) antisera as described previously (17). Coefficients of inter- and intraassay variations were 14% and 6% for AVP, and 10% and 4% for OXT, respectively. The minimum detection limit was 0.5 pg/ml for AVP and 2 pg/ml for OXT.
Plasma concentrations of ACTH and corticosterone were determined by RIA using [125I]ACTH and -corticosterone tracer. Coefficients of inter- and intraassay variations were 3% and 3% for ACTH, and 8% and 9% for corticosterone, respectively. The minimum detection limit was 2 pg/ml for ACTH and 2 pg/ml for corticosterone.
In situ hybridization histochemistry for c-fos mRNA
In situ hybridization histochemistry was performed on frozen 12-µm-thick coronal brain sections cut by a cryostat at -20 C, thawed, and mounted onto gelatin/chrome alum-coated slides. Brain tissue was stored at -80 C before cutting. The locations of the PVN and SON were determined according to coordinates given by the atlas of Paxinos and Watson (14). The sections including the PVN were chosen from plate 25 in the atlas. The sections including the SON were chosen from plate 23 in the atlas. Eight sets of four sections containing the PVN and SON were used from each rat to measure the density of autoradiography. The slides were warmed to room temperature and allowed to dry for 10 min and then fixed in 4% formaldehyde in PBS for 5 min. They were then washed twice in PBS and incubated in 0.9% NaCl containing 0.25% acetic anhydride (vol/vol) and 0.1 M triethanolamine at room temperature for 10 min. The sections were then dehydrated using a series of 70% (1 min), 80% (1 min), 95% (2 min), and 100% (1 min) ethanol solutions consecutively and delipidated in 100% chloroform for 5 min. The slides were then partially rehydrated first in 100% (1 min) and then 95% (1 min) ethanol and allowed to air dry briefly.
Hybridization was performed at 37 C overnight in a 45-µl buffer solution consisting of 50% formamide and 4x saline sodium citrate (SSC) (1x SSC = 150 mM NaCl, 15 mM sodium citrate), which contained 500 µg/ml sheared salmon sperm DNA (Sigma, St. Louis, MO), 250 µg/ml baker’s yeast total RNA (Roche Molecular Biochemicals GmbH, Mannheim, Germany), 1x Denhardt’s solution, and 10% dextran sulfate (500,000 molecular weight, Sigma). The hybridization was performed under a Nescofilm (Bando Chemical IMD, Ltd., Osaka, Japan) coverslip. A 35S-3'-end-labeled deoxyoligonucleotide that was complementary to transcripts coding for c-fos (bases 138–185 of rat c-fos nucleotides) was used. The specificity of the probes has been described previously (18, 19). A total of 1 x 106 cpm/slide for c-fos transcripts was used. After hybridization, the sections were washed for 1 h in four separate 1x SSC rinses at 55 C and for another hour in two changes of 1x SSC at room temperature. All independent experimental sections were treated simultaneously to minimize the variable effects of hybridization and wash stringency. Hybridized sections containing PVN and SON were apposed to autoradiography film (Hyperfilm, Amersham, Buckinghamshire, UK) for 14 d for c-fos transcripts. The autoradiographic images were quantified using a MCID imaging analyzer (Imaging Research, Inc., St. Catherines, Ontario, Canada). The images were captured by charge-coupled device camera (DAGE-MTI, Inc., Michigan City, IN) with x40 magnification.
The locations of the magnocellular and parvocellular divisions of the PVN and SON were chosen by the atlas. The areas of the PVN and SON were enclosed using captured images. The edges of the PVN and SON were determined by using the plates 25 and 23 of the atlas, respectively. The areas of the PVN contained both the magnocellular and the parvocellular divisions. In the present study, we did not distinguish the parvocellular division from the magnocellular division in the PVN. The mean OD of autoradiographs was measured by comparing it with simultaneously exposed [14C] microscale samples (Amersham). Because a half-life of [14C] is extremely long, [14C] is often used as the standard for quantification of the OD of autoradiographs for in situ hybridization histochemistry. The standard curve was fitted by the OD of the [14C] microscale in the same film. Slides hybridized with the c-fos probe were dipped into a nuclear emulsion (K-5, Ilford, Cheshire, UK) and exposed for a further 28 d.
Dual detection of Fos and AVP/OXT-like immunoreactivity
Deeply anesthetized animals were perfused transcardially with 0.1 M phosphate buffer (PB) (pH 7.4) containing heparin (1000 U/liter) followed by 4% paraformaldehyde and 0.2% picric acid in 0.1 M PB. The brains were then removed and divided into three blocks that included the hypothalamus. The blocks were postfixed with 4% paraformaldehyde and 0.2% picric acid in 0.1 M PB for 48 h at 4 C. The tissues were then cryoprotected in 20% sucrose in 0.1 M PB for 48 h at 4 C. Serial sections of 30 µm for dual staining for Fos and OXT/AVP were cut using a microtome. The sections were rinsed twice with 0.1 M PBS containing 0.3% Triton X-100 and incubated in 0.1 M PBS containing 0.3% Triton X-100 with 1% hydrogen peroxidase for 60 min. They were then rinsed twice with 0.1 M PBS containing 0.3% Triton X-100. The floating sections were incubated with a primary Fos antibody (sc-52, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), followed by a dilution ratio of 1:100 in 0.1 M PBS containing 0.3% Triton X-100 at 4 C for 6 d. After washing for 20 min in 0.1 M PBS solution containing 0.3% Triton X-100, the sections were further incubated for 120 min with a biotinylated secondary antibody solution (1:250), and finally with an avidin-biotin peroxidase complex (Vectastain ABC kit, Vector Laboratories, Inc., Burlingame, CA) for 120 min. The peroxidase in the sections was visualized with 0.02% diaminobenzidine in a Tris buffer containing 0.05% hydrogen peroxidase for 1.5 min. During the dual staining for AVP of OXT, they were sequentially incubated in AVP antibody (INCSTAR Corp., Stillwater, MN; diluted 1:6000) or OXT antibody (INCSTAR Corp.; diluted 1:2000) for 3 d at 4 C. The avidin-biotin peroxidase complex was made visible by using nickel sulfate.
The sections were mounted onto gelatin-coated slides, air dried, dehydrated in 100% ethanol, cleared with xylene, and then finally coverslipped. The presence of dark brown label that appeared in round structures was judged as indicative of Fos-like immunoreactivity (LI)-positive nuclei and that of violet label that appeared in spindle-shaped structures was judged as indicative of AVP- or OXT-LI. Details of the immunohistochemistry have been published elsewhere (20, 21). To count the double-labeled cells, three serial sections including the PVN and SON per animal were chosen and counted under a light microscope by two independent investigators.
Statistical analysis
A mean deviation from control (percentage) ± SEM was calculated from the results of the in situ hybridization histochemistry. Each group within an experiment was compared with the control group. The data were analyzed using a one-way fractional ANOVA followed by a Bonferroni-type adjustment for multiple comparison. The statistical significance was set at P less than 0.05.
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Results |
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). The concentrations of plasma OXT were significantly increased 15–60 min after icv administration of NMU (3 nmol/rat) in comparison with saline (Fig. 1B). The concentrations of plasma AVP and OXT were measured 15 min after icv administration of NMU (0.1, 1, and 3 nmol) or saline. The concentrations of plasma AVP and OXT were increased in a dose-related manner 15 min after icv administration (Fig. 2, A and B).
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). The concentration of plasma corticosterone was significantly increased 30 min after icv administration of NMU (3 nmol/rat) in comparison with saline (Fig. 3B). The concentration of plasma ACTH was measured 15 min after icv administration of NMU (0.1, 1, and 3 nmol/rat) or saline. The concentration of plasma ACTH was increased in a dose-related manner 15 min after icv administration of NMU (Fig. 2C
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, A and B). The icv administration of NMU induced the expression of the c-fos gene to the greatest degree at 60 min in the PVN and SON (Fig. 4, A and B). The expression of the c-fos gene in the PVN and SON after icv administration of saline did not change significantly. Microscopic observation revealed that the c-fos gene-expressing cells were distributed in the parvocellular and magnocellular divisions of the PVN throughout the ependymal cells of the third ventricle (Fig. 5, A and B), with strong signals seen predominantly in the dorsal parts of the SON (Fig. 5, C and D).
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). Thirty minutes after icv administration of anti-NMU IgG (1 µg/rat) + NMU (1 nmol/rat), the concentrations of plasma OXT and ACTH were increased and the expression of the c-fos gene had increased in the PVN and SON. However, the effects of icv administration of NMU on the secretions of OXT and ACTH were significantly reduced by pretreatment with anti-NMU IgG (Fig. 6, A and B). The changes of the expression of the c-fos gene in the PVN and the SON after icv administration of NMU were significantly attenuated by pretreatment with anti-NMU IgG (Fig. 6, C and D). Pretreatment of control serum IgG did not attenuate NMU-induced changes (Fig. 6).
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). The numerous Fos-LI cells in the parvocellular parts of the PVN showed neither OXT-LI nor AVP-LI cells (Fig. 7). In the SON, OXT-LI cells predominated in the nuclear Fos-LI region in comparison with AVP-LI cells (Fig. 8). The numbers of Fos-LI-positive cells of OXT-LI-positive cells were 591 ± 235 cells (81%) in the PVN and 529 ± 69 cells (71%) in the SON after icv administration of NMU (3 nmol/rat). After icv administration of saline, the numbers of Fos-LI-positive cells of OXT-LI-positive cells were 9 ± 5 cells (1%) in the PVN and 20 ± 9 cells (4%) in the SON. Similarly, the numbers of Fos-LI-positive cells of AVP-LI-positive cells were 16 ± 3 cells (3%) in the PVN and 49 ± 19 cells (8%) in the SON after icv administration of NMU (3 nmol/rat). After icv administration of saline, the numbers of Fos-LI-positive cells of AVP-LI-positive cells were 0 cells (0%) in the PVN and 15 ± 13 cells (2%) in the SON. The distributions of the dual-stained cells are shown in Figs. 9 and 10. The Fos-LI-positive cells of OXT-LI-positive cells were found in the anterior magnocellular and the ventral medial parvocellular divisions of the PVN and throughout the SON.
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Discussion |
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Plasma concentrations of OXT were increased significantly 15, 30, and 60 min after icv administration of NMU (3 nmol/rat). Plasma concentrations of OXT were clearly increased after icv administration of NMU in a dose-related manner (Fig. 2B). Serino et al. (22) demonstrated that centrally administered adrenomedullin (AM), a potent hypotensive peptide, caused significant increases on plasma concentration of OXT in conscious rats. The elevation of plasma concentrations of OXT reached a peak 10 min after the icv administration of AM. The effects of icv administration of NMU on the elevation of plasma concentration of OXT were longer than those of icv administration of AM. The early elevation of plasma concentration of OXT may be mediated centrally, but it is not clear whether the later effects are mediated by central effects of NMU or secondary effects such as changes in behavior (8, 9), NMU-induced hyperthermia (8, 9), and increased arterial blood pressure (1).
Plasma concentrations of AVP were increased significantly 15 and 30 min after icv administration of NMU. The magnitude of the increase of AVP was small and short in duration after icv administration of NMU. Because centrally administered NMU dose not seem to exert strong effects on AVP secretion, it is difficult to evaluate whether central NMU is involved in the regulation of AVP secretion physiologically. In addition, a high dose of centrally administered NMU (3 nmol/rat) caused a significant increase only in the plasma concentration of AVP.
Dual-immunostaining study showed that Fos-LI was very predominantly in OXT-LI cells in the anterior magnocellular and the ventral medial parvocellular divisions of PVN and throughout SON, although a few AVP-LI cells in the magnocellular divisions of the PVN and SON exhibited nuclear Fos-LI after icv administration of NMU. Our findings are in agreement with a recent study that showed that there was a high number of Fos/OXT cells in the PVN and SON after icv administration of NMU and a small proportion of Fos/AVP cells (23). These results are consistent with the result that plasma concentration of OXT was predominantly increased rather than AVP after icv administration of NMU.
Plasma concentrations of ACTH were increased significantly 30 min after icv administration of NMU (3 nmol/rat). Plasma concentrations of ACTH were increased after icv administration of NMU in a dose-related manner (Fig. 2C). The increase in plasma concentration of ACTH after icv administration of NMU may result from activation of CRH-containing neurons in the PVN. In the present study, expression of the c-fos gene and the induction of the Fos-LI after icv administration of NMU was observed in the parvocellular division of the PVN, which is known to contain CRH-producing cells. It has been demonstrated that peripheral administration of NMU8 (fragment of NMU) caused a transient increase in plasma concentrations of ACTH and a sustained elevation of plasma concentrations of corticosterone (24). It is unclear whether peripheral administration of NMU passes through blood brain barrier. However, central administration of NMU may activate the HPA axis because an elevation of plasma ACTH and corticosterone was observed 30 min after icv administration of NMU. Hanada et al. (25) reported that NMU-induced stress responses (gross locomotor activity, face-washing behavior, and grooming) were significantly abolished by pretreatment with an antagonist of CRH, 
-helical CRH, or anti-CRH IgG and that NMU did not induce locomotor activity in CRH knockout mice. Thus, central NMU may play an important role in the regulation of the HPA axis. Although NMU-producing neurons were restricted to the rostrocaudal part of the arcuate nucleus, NMU-LI fibers were widespread throughout the CNS (5). Central NMU may have multiple physiological functions in the CNS.
The present study also shows that the expression of the c-fos gene and the induction of Fos-LI in the PVN and SON were increased after icv administration of NMU. The marked increase in the c-fos gene in the PVN and SON was observed 60 min after icv administration of NMU. The expression of the c-fos gene in the PVN and SON should reflect the neural activation either directly or indirectly after icv administration of NMU. Because the expression of the NMU2R in the PVN is abundant (8), centrally administered NMU may activate PVN neurons directly through the NMU2R. It is worth noting that the c-fos gene was expressed throughout the ependymal cells of the third ventricle after icv administration of NMU. Because expression of the NMU2R in the cells is abundant (8), one possibility of an indirect pathway through which NMU may activate PVN neurons is via an unknown factor originating from the ependymal cells.
Pretreatment with anti-NMU IgG significantly attenuated NMU-induced neurosecretion and induction of the c-fos gene expression in the PVN and SON. Therefore, we confirmed that our observations after icv administration of NMU may be specific effects via NMU. However, the physiological role of endogenous NMU should be evaluated by further study, using anti-NMU IgG.
Centrally administered NMU suppressed the appetite in rats (8, 9). Food deprivation caused a decrease of the expression of the NMU gene in the hypothalamus (8). Anorectic peptides such as cholecystokinin and AM activate the central OXTergic pathway in rats (26, 27). The present study indicates that central NMU may activate OXT-producing cells in the PVN and SON in rats. The activation of the central OXTergic pathway may be involved in the suppression of feeding after central administration of NMU.
Central administration of NMU caused vasopressor and sympathetic responses in anesthetized (1) and conscious rats (8, 9). Because the PVN is known to be an integrative site for the coordination of neuroendocrine and autonomic functions (28, 29), centrally administered NMU may activate the PVN neurons that project to the regions of the brain stem and the spinal cord related to the sympathetic outflow. In the present study, we demonstrated that icv administered NMU induced the expression of the c-fos gene and the induction of Fos in the subdivision of the PVN that may project to the brain stem and spinal cord (Fig. 9).
In conclusion, centrally administered NMU may activate neuronal activity in the PVN and SON. In particular, OXT-producing magnocellular neurosecretory cells in the PVN and SON are preferentially activated by central administration of NMU.
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Acknowledgments |
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Footnotes |
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Abbreviations: AM, Adrenomedullin; AVP, arginine vasopressin; CNS, central nervous system; Fos, c-fos protein; HPA, hypothalamo-pituitary-adrenal; icv, intracerebroventricular; LI, Fos-like immunoreactivity; NMU, neuromedin U; OXT, oxytocin; PB, phosphate buffer; PVN, paraventricular; SON, supraoptic nuclei; SSC, saline sodium citrate.
Received February 20, 2002.
Accepted for publication July 25, 2002.
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