Endocrinology Vol. 138, No. 10 4096-4100
Copyright © 1997 by The Endocrine Society
Water Deprivation Increases the Expression of Pituitary Adenylate Cyclase-Activating Polypeptide Gene in the Rat Subfornical Organ1
Masayoshi Nomura,
Yoichi Ueta,
Philip J. Larsen,
Jens Hannibal,
Ryota Serino,
Narutoshi Kabashima,
Izumi Shibuya and
Hiroshi Yamashita
Department of Physiology (M.N., Y.U., R.S., N.K., I.S., H.Y.),
School of Medicine, University of Occupational and Environmental
Health, 1–1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807, Japan;
Institute of Medical Anatomy Department B (P.J.L.), University of
Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark; and
Department of Clinical Biochemistry (J.H.), Bispebjerg Hospital,
University of Copenhagen, Bispebjerg Bakke 23, DK-2400 Copenhagen NV,
Denmark
Address all correspondence and requests for reprints to: Hiroshi Yamashita, Department of Physiology, School of Medicine, University of Occupational and Environmental Health, 1–1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807, Japan.
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Abstract
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The effect of water deprivation on the expression of pituitary
adenylate cyclase-activating polypeptide (PACAP) was examined in the
rat subfornical organ (SFO), using a combination of
immunohistochemistry and in situ hybridization
histochemistry. In the euhydrated condition, PACAP-immunoreactivity
(PACAP-IR) and the expression of PACAP gene was observed in the SFO.
Water deprivation for 24 h and 48 h caused a significant
increase in PACAP gene transcripts in the SFO, compared with euhydrated
animals. Additionally, water deprivation for 48 h caused an
increase in PACAP-IR. This increase of PACAP-IR was demonstrated in
both nerve fibers and cell bodies. High correlation was found between
the localization of PACAP-IR cell bodies and PACAP messenger RNA
synthesizing cell bodies in the peripheral part of the SFO. These
results suggest that PACAP in the SFO may play a role in the humoral
and neural changes associated with the regulation of body fluid balance
after water deprivation.
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Introduction
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THE NEUROPEPTIDE pituitary adenylate
cyclase-activating polypeptide (PACAP) was isolated from ovine
hypothalamus (1). Although PACAP has been shown to be present in many
sites of the brain, it is especially abundant in the hypothalamus (2, 3). There is considerable evidence suggesting that central PACAP may be
involved in the regulation of arginine vasopressin (AVP) release and
body fluid balance (4, 5). Recent studies have demonstrated that PACAP
modulates the neuronal activity of magnocellular cells in the
hypothalamic paraventricular (PVN) (6) and the supraoptic nuclei (SON)
(7). These nuclei also express PACAP receptors (8, 9, 10). Although the
central source of PACAP to the PVN and the SON is not known, one of the
potential candidates is the subfornical organ (SFO), a
circumventricular organ involved in body fluid balance (11, 12). It is
well documented that neurons in the SFO project directly to the PVN and
the SON (13, 14, 15, 16, 17, 18). Angiotensin II (AII) is thought to be the putative
transmitter involved in this pathway. However, there are no data
suggesting the existence of PACAP in the SFO. In the present study, we
show that PACAP was expressed in the SFO under euhydrated condition,
using immunohistochemistry and in situ hybridization
histochemistry. In addition, water deprivation for 12 h, 24
h, and 48 h increased the expression of PACAP gene in the SFO.
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Materials and Methods
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Animals
Adult male Wistar rats were housed under normal laboratory
conditions (in 12-h light, 12-h dark cycle) with free access to food
and drinking water. Tap water was deprived for 48 h (n = 4)
for immunohistochemistry and for 12 h (n = 6), 24 h
(n = 6) and 48 h (n = 5) for in situ
hybridization histochemistry. In each group, the same number of rats
was used as control. Water deprivation started at 1000 h (3 h
after light on) in all groups. Dry food was available throughout the
period of water deprivation. All experimental procedures were done in
accordance with the guidelines on the use and care of laboratory
animals as set out by the Physiological Society of Japan and approved
by the animal care committee at this institution.
Immunohistochemistry
The animals were deeply anesthetized using tribromethanol (40
mg/kg; ip) and perfused via the left ventricle with a solution of
saline (0.9%) to which heparin (15,000 IU/l) was added. This perfusion
was followed by 2% paraformaldehyde and 0.2% picric acid in 0.1
M sodium phosphate buffer, pH 7.2. After fixation, the
brains were rapidly removed and postfixed in the same fixative for
24 h. After postfixation, the brains were equilibrated in PBS
containing 30% sucrose for 48 h at 4 C and then sectioned at 40
µm in a cryostat, and the resulting sections were collected as
free-floating sections in PBS. Immunohistochemical visualization of
PACAP-immunoreactivity (PACAP-IR) was carried out on free-floating
sections with avidin-biotin-horseradish peroxidase methods, as
described previously, using an N-terminally directed antibody (diluted
1:5, mouse monoclonal no. Mab JHH1) (3, 19). The monoclonal antibody
used here displays equal affinity to PACAP38 and PACAP27 recognizing an
epitope between amino acid 6–16 and has no affinity for PACAP-related
peptide (PRP), VIP, PHI or other known structurally related peptides
(3). Because PACAP stained many specific areas in the hypothalamus, the
rest of the brain sections were used as positive controls. As controls,
sections were routinely incubated with antibodies preabsorbed with
PACAP38 and PACAP27 (20 µg/ml), which abolished all specific
staining.
In situ hybridization histochemistry
After dehydration the animals were decapitated and the brains
were rapidly removed, frozen on dry ice, and stored at -80 C. Trunk
blood was collected in heparinized tubes for the measurement of plasma
osmolality and sodium concentration. Frozen transverse sections were
cut at 12 µm in a cryostat and mounted onto gelatin/chrome
alum-coated slides. The sequences of oligodeoxynucleotides for rat
PACAP were complementary to bases 813–861 of the rat PACAP
complementary DNA (cDNA), which is the region encoding a part of PRP
(20). The specificity of the probe has been described previously (19).
We have checked the specificity of the signals, using other probes
complementary to bases 1023–1073 of the rat PACAP cDNA, which is the
region encoding a part of PACAP, and bases 813–861 of the ovine PACAP
cDNA encoding a part of PRP (21). The specificity of signals was also
confirmed by using a sense probe for probes complementary to bases
813–861 of the rat and ovine PACAP cDNA. The effect of addition of a
100-fold excess of the unlabeled each probe (complementary to bases
813–861 and 1027–1073 of the rat PACAP cDNA and bases 813–861 of the
ovine PACAP cDNA) was examined. The probe was 3'-end labeled using
terminal deoxynucleotidyl transferase (TdT) and [35S]
dATP. In situ hybridization procedures have been described
in detail previously (22). In brief, sections were fixed in 4%
formaldehyde for 5 min and incubated in saline containing 0.25% acetic
anhydride (vol/vol) and 0.1 M triethanolamine (TEA) for 10
min, then dehydrated and delipidated in chloroform. Hybridization was
carried out overnight at 37 C in 45 µl hybridization buffer
containing 50% formamide and 4 x SSC (1 x SSC = 150
mM NaCl and 15 mM sodium citrate), 500 µg/ml
sheared salmon sperm DNA (Sigma, St. Louis, MO), 250 µg/ml baker’s
yeast total RNA (Boehringer Mannheim GmbH, Mannheim, Germany), 1
x Denhardt’s solution (0.02% Ficoll, 0.02% polyvinylpyrrolidone,
and 0.02% BSA) and 10% dextran sulfate (500,000 mol wt, Sigma) under
a Nescofilm (Bando Chemical IMD, Ltd., Osaka, Japan) coverslip. Total
counts of 1 x 106 cpm/slide were used. After
hybridization, sections were washed for 1 h in four changes of
1 x SSC at 55 C and for a further 1 h in two changes of
1 x SSC at room temperature. Hybridization sections were apposed
to autoradiography (Hyperfilm, Amersham, Buckinghamshire, UK) for 7
days. Quantitative image analysis was undertaken with an MCID Image
Analysis System (Imaging Research Inc., Ontario, Canada). The mean
optical density of autoradiographs was measured by comparison with
simultaneously exposed [14C] microscale (Amersham). The
standard curve was fitted by the optical density of [14C]
of the autoradiographs in every film. Slides hybridized to the
PACAP-probe were dipped in nuclear emulsion (K-5, Ilford, Cheshire, UK)
and exposed for 4 weeks. All sections were treated simultaneously
throughout to minimize the effects of variations in hybridization and
wash stringency.
Statistics
The results obtained from in situ hybridization
histochemistry are presented as the mean change from controls
(percentage) ±SEM. Statistical analysis was carried out
using one-way ANOVA. In respect of body weight, the subtraction of the
body weight at the beginning and the end of water deprivation were used
for the statistical analysis because the means of body weights at the
beginning of water deprivation in each group were different. A
P < 0.05 was considered statistically significant.
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Results
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Under euhydrated condition, PACAP-IR and PACAP gene expression
were observed in the SFO (Figs. 1A
, 2, A and C,
3A, and 4,
A, D, and G). In euhydrated animals, PACAP-IR fibers were observed
throughout the SFO with a preponderance in the perimeter of the organ.
PACAP-IR fibers were either thick and smooth or fine caliber endowed
with varicosities, a morphology corresponding to dendrites and axons,
respectively. PACAP-IR fibers in the central region of the SFO were
increased 48 h after water deprivation (Fig. 1B). In addition,
PACAP immunopositive cells were observed along the peripheral region of
the SFO 48 h after water deprivation (Fig. 1, B, C, and D).
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Figure 1. Brightfield photomicrographs of PACAP-IR in the
SFO of the rat using diaminobenzidine (DAB) as the chromogen. A–D,
Sections from euhydrated rat and 48 h dehydrated rat,
respectively. The scale bars represent 100 µm in A and B.
Inset in B is shown at a higher magnification in C. C,
PACAP-IR fibers that were either thick (arrows) and
smooth or fine (arrowhead) in the peripheral region of
the SFO from a dehydrated rat. The scale bar represents
50 µm in C. Inset in C is shown at a higher
magnification in D. D, PACAP-IR cell bodies (arrow) in
the ventral portion of the SFO. The scale bar represents
25 µm in D.
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Figure 2. Representative autoradiographs of slides
hybridized to a 35S-labeled oligodeoxynucleotide probe for
the rat PACAP. A, Section from euhydrated rat, B is section from
48 h dehydrated rat with a 35S-labeled
oligodeoxynucleotide probe complementary to bases 813–861 of the rat
PACAP. Insets in A and B are shown at a higher magnification in C and
D, respectively. E, Section hybridized to a 35S-labeled
oligodeoxynucleotide probe complementary to bases 813–861 of the rat
PACAP with addition of a 100-fold excess of unlabeled probe from
48 h dehydrated rat. F, Section hybridized to a
35S-labeled sense probe (bases 813–861 of the rat PACAP)
from 48 h dehydrated rat. The scale bars represent
1 mm.
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Twelve hours of water deprivation did not induce any changes in PACAP
transcripts in the SFO (Figs. 3B and 5).
Twenty-four hours of water deprivation induced a significant increase
(144 ± 13% of the control value) in PACAP transcripts in the SFO
(Figs. 3C and 5). Forty-eight hours of water deprivation induced a
further increase (297 ± 35% of the control value;
P < 0.01) in PACAP transcripts in the SFO (Figs. 2
, B and D; 3D; 4, B, C, E, F, H, and I;
and 5). Microscopic examination of the emulsion dipped hybridized
sections revealed that both the number and intensity of cells labeled
with the PACAP probes increased in the SFO in the dehydrated rats (Fig. 4, B, C, E, F, H, and I). Typical examples in euhydrated and 48 h
water-deprived rats are shown in Fig. 4. Panels A–C, D–F, and G–I
are sections hybridized to a 35S-labeled
oligodeoxynucleotide probes complementary to bases 813–861, 1023–1073
of the rat PACAP and bases 813–861 of the ovine PACAP, respectively.
These three different oligodeoxynucleotide probes gave rise to
identical labeling on the sections from euhydrated, 12, 24, 48 h
water-deprived rats. The PACAP gene was expressed mainly in the
peripheral region of the SFO after 24 and 48 h dehydration. The
location of the induced PACAP gene (Fig. 4, B, C, E, F, H, and I) was
consistent with that of the PACAP-IR (Fig. 1, B, C, and D).
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Figure 3. Representative autoradiographs of slides
hybridized to a 35S-labeled oligodeoxynucleotide probe
(A–D) complementary to bases 813–861 of the rat PACAP and with
addition of a 100-fold excess of unlabeled probe (E–H) in the SFO. A
and E, B and F, C and G, and D and H are sections from euhydrated, 12,
24 and 48 h water-deprived rats, respectively. A couple of
sections including the SFO are adjacent sections obtained from same
animal. The scale bar represents 1 mm.
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Figure 5. The effects of 12, 24, and 48 h after water
deprivation on PACAP transcripts prevalence in the SFO. Values
represent the mean ± SEM. Number of rats was six in
all groups except 48 h after water deprivation (n = 5).
Statistical analysis was carried out using one-way ANOVA: *,
P < 0.05; **, P < 0.01 compared
with each control.
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Figure 4. Representative dark- (A, B, D, E, G, and H) and
bright- (C, F, and I) field photomicrographs of emulsion-dipped slides
of the SFO hybridized to a 35S-labeled three different
oligodeoxynucleotide probes for PACAP. A–C, D–F, and G-I are sections
hybridized to a 35S-labeled oligodeoxynucleotide probes
complementary to bases 813–861, 1023–1073 of the rat PACAP and bases
813–861 of the ovine PACAP, respectively. A, D, and G are sections
from euhydrated rat and B, E, and H are sections from 48 h
dehydrated rat. B and C, E and F, and H and I are the same section,
respectively. C, F, and I were stained using cresyl fast violet. The
scale bar represents 100 µm.
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The signals were completely abolished with addition of a 100-fold
excess of unlabeled probe complementary to bases 813–861 of the rat
PACAP (Figs. 2E and 3, E–H). No signal was obtained with sense probe
for the probe complementary to bases 813–861 of the rat PACAP (Fig. 2F). The identical results were also obtained from the other probes
complementary to bases 1023–1073 of the rat PACAP and bases 813–861
of the ovine PACAP.
Body weights of the animals, plasma osmolalities, and plasma
concentration of sodium are summarized in Table 1. Although water deprivation for 12
h did not result in any change in plasma osmolality and sodium
concentration, a significant increase in both plasma osmolality
(P < 0.01) and plasma sodium concentration
(P < 0.05) after water deprivation for 24 h and
48 h. The body weights of animals decreased significantly after
water deprivation for 12 h, 24 h, and 48 h
(P < 0.01).
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Discussion
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The present study has provided the first demonstration that the
PACAP gene was expressed in the SFO under euhydrated condition. In
addition, water deprivation induced a significant increase in PACAP-IR
and in the PACAP transcripts in the SFO. Several anatomical and
electrophysiological studies have revealed that the PVN and the SON
receive direct afferent projections from the SFO (13, 14, 15, 16, 17, 18). Combined
with the finding that these nuclei contain PACAP receptors (8, 9, 10) and
that magnocellular neurons alter their discharge to PACAP in both the
SON and the PVN (6, 7), the present results suggest that PACAP in the
SFO may be involved in this afferent pathway. Further supporting the
existence of PACAP in the SFO efferents is the observation that all
hypothalamic nuclei innervated by the SFO also contain a high density
of PACAP-IR nerve fibers and terminals (3, 15). It is interesting to
note that the SFO cells expressing the PACAP gene are located
predominantly around the outer edge of the SFO, a region that has been
shown to contain neurons retrogradely labeled after tracer injections
in the SON and the PVN (16, 17). Using a method combining retrograde
tracing with c-fos immunocytochemistry, it has been shown
that neurons of the outer annular zone of the SFO projecting to the PVN
also react with increased c-fos expression in response to
the osmotic stimulus of an ip injection of hypertonic saline (23).
Thus, it seems possible that PACAP may constitute one of the
transmitters involved in a pathway conveying information about osmotic
perturbations from the SFO to the PVN. Murase et al. (4)
suggested that one of central sources of PACAP to the PVN and the SON
may be the PACAP-expressing cells in the arcuate nucleus (ARC) that are
up-regulated by water deprivation. As the neurons in the ARC project to
the SFO, the PVN, and the SON (24, 25), it is possible that PACAP may
be a key neuropeptide in these networks for regulating AVP release and
body fluid balance. Although the data presented in this study do not
exclude this possibility, it also suggests that the SFO may be an
important site of origin of PACAP projections to the PVN and the SON.
Neither the origin nor the projection pathways of PACAP-IR neurons of
the SFO were determined in the present study. Future studies await to
determine whether PACAP-IR fibers and terminals within the SFO
originate from intrinsic neurons or they represent terminal fibers
originating outside the SFO. It is possible that neurons of the medial
parvicellular zone of the PVN constitute a PACAP containing pathway to
the SFO because this region is known to project to the SFO (26), as
well as to synthesize PACAP (19).
We performed in situ hybridization using three different
35S-labeled oligodeoxynucleotide probes in the present
study. These sequences of oligodeoxynucleotide probes were
complementary to bases 813–861 of the rat and ovine PACAP cDNA
encoding a part of PRP and 1023–1073 of the rat PACAP cDNA encoding a
part of PACAP. The cDNA encoding for rat PACAP precursor contains the
regions encoding for PACAP38 and PRP. These three different
oligodeoxynucleotide probes gave rise to identical labeling on the
sections from euhydrated, 12, 24, 48 h water-deprived rats. The
specificity of signals were also confirmed by using sense probes and
the addition of a 100-fold excess of the unlabeled probes in the
present study.
Smith et al. (27) have reported that hypertonic saline
induced c-Fos expression in the peripheral region of the SFO. On the
other hand, hypovolemia induced c-Fos expression in the central region
of the SFO, a region that has peripherally accessible binding sites for
AII (28). In the present study, the expression of PACAP gene was
observed in the peripheral region of the SFO 24 and 48 h after
dehydration. Thus, significant increases of PACAP messenger RNA (mRNA)
synthesis in the SFO were not observed until 12 h of dehydration.
However, PACAP gene expression in the SFO seems to be tightly coupled
to perturbations in plasma osmolality because up-regulation of PACAP
mRNA synthesis in the SFO carefully followed plasma osmolality and
increased sodium levels, both of which appeared unaffected by the
applied dehydration paradigm for the first 12 h. Therefore,
hyperosmolality may be one of the important factors that stimulate
PACAP gene expression in the SFO after dehydration. It should be noted
that water deprivation induces a reduction of intravascular and
extravascular volumes of the animals and evokes various changes
associated humoral factors. The possibility exists that hypovolemic and
humoral changes during water deprivation may also effect the induction
of PACAP gene expression in the SFO.
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Footnotes
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1 This study was supported by Grants-in-Aid for Scientific Research,
Nos. 08457022 and 07507004 (for H.Y.) from the Ministry of Education,
Science, Sports and Culture, Japan; a Special Grant by the Ministry of
Labor for Occupational Health Studies and the Salt Science Research
Foundation; and grants from the Danish Medical Research Council
(12–1642-1), the Danish Diabetes Association, the NOVO-Nordisk
Foundation, the Foundation for the Advancement of Medical Science, the
Danish Medical Association, and the Danish Biotechnology program for
Cellular Communication. 
Received March 7, 1997.
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E. R. Gillard, M. Leon-Olea, S. Mucio-Ramirez, C. G. Coburn, E. Sanchez-Islas, A. de Leon, H. Mussenden, L. G. Bauce, Q. J. Pittman, and M. C. Curras-Collazo
A Novel Role for Endogenous Pituitary Adenylate Cyclase Activating Polypeptide in the Magnocellular Neuroendocrine System
Endocrinology,
February 1, 2006;
147(2):
791 - 803.
[Abstract]
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D. Vaudry, B. J. Gonzalez, M. Basille, L. Yon, A. Fournier, and H. Vaudry
Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions
Pharmacol. Rev.,
June 1, 2000;
52(2):
269 - 324.
[Abstract]
[Full Text]
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Abstract
Introduction
