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Distribution of Secretin Receptors in the Rat Central Nervous
System: an in situ Hybridization Study
Zsuzsanna E. Tóth &Andrea Heinzlmann &Hitoshi Hashimoto &Katalin Köves
Received: 2 July 2012 /Accepted: 24 September 2012 / Published online: 11 October 2012
#Springer Science+Business Media New York 2012
Abstract Secretin shows a wide distribution in the brain.
Functional significance of central secretin is stressed since it
has been associated with autism and schizophrenia. The
presence of the secretin receptor was previously demonstrat-
ed in the brain by different methods. Neurons in the cere-
bellum, hypothalamic paraventricular and supraoptic nuclei,
and in the vascular organ of lamina terminalis were shown
to express secretin receptor mRNA by using in situ hybrid-
ization with digoxigenin-labeled probe. In this work, we
used a very sensitive radioactive in situ hybridization tech-
nique and systematically mapped the expression of secretin
receptor mRNA in the brain. The densest labeling was
observed in the nucleus of solitary tract and in the latero-
dorsal thalamic nucleus, where decreasing number of recep-
tors was seen in the vascular organ of lamina terminalis, and
the lateral habenular complex, and then in the supraoptic
nucleus. Only a few scattered labeled cells were observed in
the median frontal gyrus, entorhinal cortex, hypothalamic
paraventricular nucleus, perifornical region, lateral hypotha-
lamic area, head of the caudate nucleus, spinal trigeminal
nucleus, and cerebellum. Secretin receptor mRNA showed a
far wider distribution than was known before, suggesting a
more significant functional relevance than thought earlier.
Keywords Brain stem .Forebrain .In vitro transcription .
Radioactive labeling .Mapping
Abbreviations
BNST Bed nucleus of stria terminalis
Bp Base pair
cAMP Cyclic adenosine monophosphate
CRH Corticotropin-releasing hormone
GABA Gamma-aminobutyric acid
ICV Intracerebroventricular
IN Intranasal
IV Intravenous
PBS Phosphate-buffered saline
PCR Polymerase chain reaction
NST Nucleus of solitary tract
PV Paraventricular nucleus
SO Supraoptic nucleus
SSC Sodium chloride–sodium citrate buffer
UTP Uracil triphosphate
VOLT Vascular organ of lamina terminalis
Introduction
Secretin, one of the “so-called”gastrointestinal peptides,
was first described in enteroendocrine S cells of the duode-
num and in Langerhans islets (Sundler and Hakanson 1988).
With the use of radioimmunoassay, secretin was also found
in several regions of the central nervous system including
the thalamus, hypothalamus, olfactory bulb, cerebral cortex,
septum, striatum, hippocampus, midbrain, pons, and medul-
la (Charlton et al. 1981). Secretin and its mRNA were also
J Mol Neurosci (2013) 50:172–178
DOI 10.1007/s12031-012-9895-1
Z. E. Tóth
Neuromorphological and Neuroendocrine Research Laboratory,
Department of Anatomy, Histology and Embryology,
Semmelweis University and the Hungarian Academy of Sciences,
1094 Budapest, Hungary
A. Heinzlmann :K. Köves (*)
Department of Human Morphology and Developmental Biology,
Semmelweis University,
Tűzoltó u. 58,
1094 Budapest, Hungary
e-mail: koves.katalin@med.semmelweis-univ.hu
H. Hashimoto
Laboratory of Medicinal Pharmacology,
Graduate School of Pharmaceutical Sciences, Osaka University,
Yamada-oka,
Suita, Osaka, Japan
shown in the Purkinje cells of the cerebellar cortex (Yung
et al. 2001).
In our laboratory, using immunohistochemistry, we ob-
served secretin immunopositive elements in various parts of
human, cat, and rat central nervous systems including the
Purkinje cells of the cerebellar cortex, central cerebellar nu-
clei, pyramidal cells of the motor cortex, hippocampus, supe-
rior olivary nucleus, trapezoid body in the pons, and in the
sensory ganglia (Koves et al. 2002,2004; Heinzlmann et al.
2011). It has also become evident that secretin is synthetized
in the hypothalamic supraoptic (SO) and paraventricular (PV)
nuclei (Welch et al. 2004; Chu et al. 2009), and it regulates
water homeostasis (Chu et al. 2009). It was also shown that
intravenous (IV), intracerebroventricular (ICV), or intranasal
(IN) administration of secretin influenced the behavior of rats,
mice, and humans. In rats, its ICV administration decreased
the open field locomotor activity and the novel object ap-
proach (Charlton et al. 1983). In a special mouse model
(Japanese waltzing mice), ICV and IN secretin attenuated the
hyperactive repetitive movement (Koves et al. 2011;
Heinzlmann et al. 2012). In autistic children, a single IV
secretin injection improved eye contact, alertness, and expan-
sion of expressive language (Horvath et al. 1998).
Question arises concerning the site of action of secretin.
It is likely that secretin exerts its effect in places where (1) it
induces neural activity (appearance of c-fos) and (2) where
its receptors occur.
1. IV infusion of secretin into rats induced c-fos gene ex-
pression in the central amygdala, area postrema, the bed
nucleus of the stria terminalis (BNST), external lateral
parabrachial nucleus, and SO (Goulet et al. 2003). After
ICV administration of secretin, many regions, such as
several brain stem, hypothalamic, and limbic structures
(septum and amygdala) and the medial bank of the ante-
rior prefrontal, orbitofrontal, and piriform cortex, showed
activation of Fos protein in awake, freely moving rats
(Welch et al. 2003). It is clear from the above-mentioned
data that secretin influences c-fos expression in the struc-
tures that are involved in behavior, stress adaptation, and
visceral responses.
2. Secretin receptors in the central nervous system were first
demonstrated by Fremeau and his coworkers (1983).
They applied radiolabeled secretin binding assay using
tissue homogenate. The highest level of the secretin re-
ceptor was observed in the cerebellum, and a gradually
decreasing amount was detected in the frontal cortex,
striatum, hippocampus, thalamus, hypothalamus, medul-
la/pons, and midbrain. The above-mentioned data sug-
gested a relationship between secretin receptors and
gamma-aminobutyric acid (GABA) receptors. Indeed,
two decades later, it was demonstrated that, in the cere-
bellum, secretin facilitated the GABA-ergic inhibitory
input onto Purkinje cells via a postsynaptic and cAMP-
dependent mechanism as a retrograde messenger (Yung et
al. 2001,2006). An in vitro autoradiographic investiga-
tion suggested a different distribution (Nozaki et al.
2002). The radiolabeled secretin was bound in higher
concentration to the nucleus of solitary tract (NST) than
in the laterodorsal thalamic and accumbens nuclei. Mod-
erate binding was found in the orbital, cingulate, piriform,
frontal, parietal, and entorhinal cortices, caudate/putamen,
hippocampus, lateral septal nucleus, olfactory bulb,
amygdala, hypothalamus, pineal body, pituitary gland,
dorsal raphe nucleus, locus coeruleus, and cerebellum.
Weak binding was seen in the corpus callosum. A re-
search group (Tay et al. 2004) studied expression levels
of secretin and secretin receptor mRNA in several brain
regions of rat ranging in age from postnatal days 7 to 60
by quantitative real-time PCR. Both secretin and its re-
ceptor showed highest expression levels at postnatal days
7 and 14 compared to later time points. Interestingly,
secretin receptor mRNA was most abundant in the cere-
bellum, while secretin mRNA expression was strongest in
the NST. In situ hybridization using digoxigenin-labeled
probe was used to identify secretin receptor mRNA-
expressing neurons in the Purkinje and basket cells of
the cerebellum and in the deep cerebellar nuclei (Yung
et al. 2006), as well as in the magno- and parvocellular
PV, SO, and in the vascular organ of the lamina terminalis
(VOLT) (Chu et al. 2009; Lee et al. 2010). In our recent
study, using radioactive labeling of the secretin receptor
probe, we described secretin receptor mRNA in all layers
of the cerebellar cortex of male rats (molecular, Purkinje
cell, and granule cell layers in both vermis and hemi-
spheres) (Heinzlmann et al. 2012).
The aim of our present work was to precisely map the
secretin receptor mRNA-expressing neurons in the forebrain
and brain stem by in situ hybridization histochemistry, giving
a high morphological resolution. We applied radioactive la-
beling of the secretin receptor probe by [
35
S]-uracil triphos-
phate (UTP) incorporated by in vitro transcription to achieve a
maximal sensitivity.
Experimental Procedures
Animals
Adult male Wistar rats (Semmelweis University, Budapest,
Hungary) weighing approximately 400 g were used for our
experiments. The rats were kept in a temperature-controlled
vivarium (22 ± 2 °C). The lights were on at 7:00 a.m. and off
at 7:00 p.m. The animals were fed with standard lab chow and
tap water ad libitum. Five animals were decapitated; the brains
J Mol Neurosci (2013) 50:172–178 173
were immediately removed, frozen on dry ice, and stored
at −70 °C until use. The animals were treated according to
the rules of the European Communities Council Directive
(86/609/EEC), permission no. 22.1/1158/2010.
Tissue Sectioning
The tissue blocks were warmed up to −20 °C, and 12-μm-
thick serial coronal sections were cut on cryostat (Cryotome,
Thermo Shandon, Pittsburg, PA). The sections were mounted
on Superfrost Plus slides (Thermo Scientific, Budapest,
Hungary), dried on a hot plate (37 °C), and then stored
at −70 °C again until use.
In situ Hybridization
Probe Preparation
The preparation of the probe was a critical step for the suc-
cessful assay. A vector (CDM8) containing the complete rat
secretin receptor cDNA (1,796 bp) was kindly provided by Dr.
Hashimoto and Dr. Baba (Ishihara et al. 1991). A 453-bp-long
fragment according to 783–1,235 bp of the original cDNA
was subcloned into a pBluescript II SK (+) vector and verified
by sequencing. Antisense and sense cRNA probes, labeled by
[
35
S]-UTP and used for in situ hybridization, were produced
by in vitro transcription using the MAXIscript in vitro tran-
scription kit (Invitrogen, Budapest, Hungary).
Hybridization and Visualization
Before hybridization, sections were fixed in 4 % paraformal-
dehyde dissolved in phosphate-buffered saline (PBS) (pH
7.4), washed in PBS, and then treated with 0.25 % acetic
anhydride in 0.1 M triethanolamine HCl (pH 8.0) for
10 min. The sections were then rinsed in ×2 sodium chlo-
ride–sodium citrate buffer (SSC, pH 7.0), dehydrated and
delipidated in a subsequent series of 70-85-95-100-95 % eth-
anol, and finally air dried. Hybridization was performed over-
night at 55 °C with 10
6
cpm/slide radioactively labeled
secretin receptor riboprobe in a humid chamber. On the fol-
lowing day, the sections were washed in ×4 SSC buffer for 4 ×
5 min at room temperature; then, they were treated in RnaseA
(20 μg/ml; Sigma, Budapest, Hungary) buffer (pH 8.0) con-
taining 500 mM NaCl, 10 mM Tris–HCl, and 0.25 mM ethi-
lenediaminetetraacitic acid for 30 min at 37 °C and then for
5 min in each of the following buffer solutions: ×2, ×1, and
×0.5 SSC at room temperature and finally in ×0.1 SSC at
65 °C for 2 × 30 min. Then, the slides were let to cool down
and were washed in PBS. The slides were dipped into NTB
nuclear track emulsion (Carestream Health Inc., Rochester,
NY). After 8 weeks of exposition time at 4 °C in dark, the
reaction was developed using Kodak Dektol developer and
fixer (Sigma) at 18 °C. The slides were counterstained with
Giemsa solution, dried, and coverslipped with DePeX (all
from Sigma).
Results
Secretin Receptors in the Forebrain
With the use of antisense probe, secretin receptors were found
in many regions of the forebrain; however, there was no signal
using the sense probe. We observed a considerable number of
positive cells in the VOLT (Fig. 1a, b). Secretin receptors were
also found in the hypothalamic magnocellular nuclei, SO
(Fig. 1c, d), and PV (Fig. 1e, f), but not in the anterior
commissural nucleus. The number of silver grain containing
cells was greater in the SO than in the PV.
Scattered labeled cells were seen in the median frontal
gyrus, head of the caudate nucleus, perifornical region, ento-
rhinal cortex, and lateral hypothalamic area (not shown).
There was no labeling in the BNST, septum, amygdala, and
Fig. 1 Microphotographs demonstrating secretin receptor mRNA ex-
pression in hypothalamic frontal sections. a,bVascular organ of the
lamina terminalis; c,dsupraoptic nucleus; e,fparaventricular nucleus.
b,d, and fHigh power details of a,c, and e, respectively. Arrows
indicate secretin receptor mRNA-expressing cells. Asterisks indicate
same structures in aand b,c, and das well as in eand f, respectively.
3Vthird ventricle, Ffornix, OX optic chiasm, PRE preoptic recess, PV
hypothalamic paraventricular nucleus, SO supraoptic nucleus, VOLT
vascular organ of the lamina terminalis. Scale 0150 μmina,c, and e
and 30 μminb,d, and f
174 J Mol Neurosci (2013) 50:172–178
hippocampus. In the forebrain, the densest labeling was seen
in the laterodorsal thalamic nucleus (Fig. 2a, b). Significant
number of labeled cells was seen in the lateral habenula
(Fig. 2c, d).
Secretin Receptors in the Brain Stem
The density of secretin receptors was very high in NST
(Fig. 3a, b). A few weakly labeled cells were also seen in
the second-order sensory neurons of the spinal trigeminal
nucleus (not shown).
Discussion
On the basis of previous results (Yung et al. 2001,2006;
Koves et al. 2002,2004), it is appropriate to accept secretin
as a neuropeptide synthetized in both central and peripheral
nervous systems. As it was mentioned in the introduction,
secretin receptors in the central nervous system were demon-
strated by the following several methods: radiolabeled secretin
binding assay using tissue homogenate, in vitro autoradio-
graphic investigation, quantitative real-time PCR, and in situ
hybridization using digoxigenin-labeled probe (Fremeau et al.
1983; Nozaki et al. 2002; Tay et al. 2004). Our paper is the
first in which secretin receptors were demonstrated in the
forebrain and brain stem using radioactive in situ hybridiza-
tion. This method is very sensitive and gives high morpho-
logical resolution, enabling identification of the cell groups
where secretin receptor mRNA is present.
The question arises: what may be the role of secretin recep-
tors in the various regions of the forebrain and brain stem. One
of the regions, where we observed strong in situ hybridization
signal, was the laterodorsal thalamic nucleus. This is in agree-
ment with the earlier findings (Nozaki et al. 2002). The later-
odorsal thalamic nucleus receives information from the visual
cortex and projects to the limbic system. It plays a role in spatial
learning and memory (van Groen et al. 2002).
A very dense secretin receptor mRNA labeling was also
seen in the NST, confirming previous data (Nozaki et al.
2002; Tay et al. 2004). The NST relays gustatory, olfactory,
and visceral sensory information toward upper brain centers.
Afferent fibers from cranial nerves VII, IX, and X convey
taste to its rostral portion and general visceral sense to its
caudal part. This nucleus is also an important autonomic
regulatory center (Garcia-Diaz et al. 1988). Secretin there-
fore may influence all of the above-mentioned functions
through its receptors in the NST.
VOLT is another region where secretin and its receptors
are present. As it was shown, secretin through the magno-
cellular neurons in the PV and SO, which also express
secretin receptor mRNA, has a crucial role in the water
homeostasis (Chu et al. 2009). The strong secretin receptor
mRNA expression in the VOLT supports this hypothesis.
VOLT possesses osmoreceptors and is involved in osmoti-
cally stimulated vasopressin release, as well as in central
hyperosmolality-induced increases of sympathetic nerve ac-
tivity and arterial blood pressure (McKinley et al. 2004; Shi
et al. 2007). Secretin increased vasopressin release from
hypothalamic explants, and dehydration evoked secretin
release from the posterior pituitary to the systemic circula-
tion (Chu et al. 2009). This research group also showed
secretin and secretin receptor transcripts in the VOLT using
real-time PCR and digoxigenin-labeled riboprobe in in situ
hybridization assay (Lee et al. 2010). They also demon-
strated that angiotensin II exerts its effect through secretin and
its receptors on water homeostasis using secretin and secretin
knockout mice. Our morphological results support this
hypothesis.
Fig. 2 Microphotographs demonstrating secretin receptor mRNA ex-
pression in the laterodorsal thalamic nucleus in the forebrain. a,bLater-
odorsal thalamic nucleus; c,dlateral habenular nucleus. b,dHigh power
details of aand c, respectively. Arrows show secretin receptor mRNA-
expressing cells. Asterisks indicate same structures in aand bas well as in
cand d,respectively.3Vthird ventricle, Hipp hippocampus, LHN lateral
habenular nucleus, LD laterodorsal thalamic nucleus. Scale 0150 μmina
and cand 30 μminband d
Fig. 3 Microphotographs demonstrating secretin receptor mRNA ex-
pression in the medulla oblongata (a,b). bHigh power detail of a.Arrows
show secretin receptor mRNA-expressing cells. Asterisks indicate same
structures in aand b.4Vfourth ventricle, GCL granule cell layer, MOL
molecular cell layer, NST nucleus of the solitary tract. Scale 0150 μmina
and cand 30 μminband d
J Mol Neurosci (2013) 50:172–178 175
In this study, we not only confirmed previous data but also
identified so far unrecognized regions in the brain, where
secretin receptor mRNA is expressed. These are the lateral
habenular nucleus, perifornical and lateral hypothalamic
areas, and spinal trigeminal nucleus. The central axons of
the secretin immunoreactive primary sensory neurons of the
trigeminal ganglion terminate in the spinal trigeminal nucleus
(Heinzlmann et al. 2011). This observation well correlates
with our new observation that this nucleus expresses secretin
receptors. Our morphological data support the physiological
observation that secretin counteracts the analgesic effect of
morphine (Babarczy et al. 1995).
In our recently published paper (Heinzlmann et al. 2012),
we described many strongly labeled cells in the granule cell
layer, a few scatteredcells in the molecular cell layer, and only
very rare labeling in the Purkinje cell layer of the cerebellar
cortex in male rats. The labeling in the granule cell layer
suggests that the receptors may also be present in those
GABA-ergic cells which participate in forming the cerebellar
glomeruli. Yung and his coworkers (2001, 2006) described
strong secretin receptor mRNA expression in the Purkinje
cells, a weaker in the basket cells in the molecular cell layer,
and no labeling in the granule cell layer. However, they used
nonradioactive in situ hybridization method and worked on
Sprague–Dawley rats, while we used radioactive in situ hy-
bridization and Wistar rats. Additionally, their probe was
specific to the region according to 213–639 bp of rat secretin
receptor cDNA, (GenBank accession no. NM031115), while
ours contained a nonoverlapping region (783–1,235 bp).
Therefore, the different results can also be explained by the
existence of putative splice variants of the secretin receptor in
the brain. Although splice variants were not yet identified in
VOLT
P
CC
OX
P
AC
CC
OX
PV
LHN
Cer
NST
CPu LD
AC
Cer
Lateral 0.10 mm
Lateral 0.40 mm
Lateral 2.62 mm
Lateral 1.40 mm
POT
AC
SO
CC
LH
FNST
Cer
LD
Sp5
CC
CPu
Fig. 4 Schematic illustration of the occurrence and density of secretin
receptor mRNA expression in sagittal sections of the brain, according to
stereotaxic coordinates of Paxinos and Watson (2007). Distance from the
midline is labeled in millimeters. The number of asterisks indicates the
density of the signal. AC anterior commissure, CC corpus callosum, Cer
cerebellar hemisphere. Single and quadruple asterisks indicate molecular
and granule cell layers, respectively; CPu caudate putamen, Fperifornical
area, LH lateral hypothalamus, LHN lateral habenular nucleus, LD later-
odorsal thalamic nucleus, OT optic tract, OX optic chiasm, Ppituitary, PV
hypothalamic paraventricular nucleus, Sp5 spinal trigeminal nucleus,
NST nucleus of the solitary tract, SO supraoptic nucleus, VOLT vascular
organ of the lamina terminalis. The data concerning the cerebellum
derives from the paper of Heinzlmann et al. (2012)
Table 1 Summary of
the distribution of
secretin receptor
mRNA-expressing
neurons in the forebrain,
brain stem, and
cerebellum
Semiquantitative analy-
sis of the in situ
hybridization signal:
+ occasional, ++ week,
+++ moderate,
++++ strong
labeling, −no labeling.
The data concerning the
cerebellum were
published in our previ-
ous paper (Heinzlmann
et al. 2012)
Forebrain structures
median frontal gyrus +
entorhinal cortex +
VOLT +++
SO ++
PV +
perifornical area +
lateral hypothalamus +
BNST −
septum −
laterodorsal thalamus ++++
lateral habenular nucleus +++
amygdala −
hippocampus −
head of caudate nucleus +
Brain stem structures
nucleus of the solitary tract ++++
spinal trigeminal nucleus +
Cerebellum
vermis +
molecular cell layer +
granule cell layer ++++
176 J Mol Neurosci (2013) 50:172–178
healthy tissues, they were demonstrated in bronchopulmonary
carcinoid tumors by autoradiography and real-time PCR
(Korner et al. 2008). Since there were other areas in the brain,
where secretin binding was found by others like in the septum,
amygdala, and hippocampus (Fremeau et al. 1983;Nozakiet
al. 2002), we did not see any labeling. Therefore, we suppose
that the expression of the secretin receptor in these areas was
below the detection level in rats (400 g bw) we used. Nozaki
and Fremeau examined much younger animals, with a body
weight of 160–180 and 200–250 g, respectively (Fremeau et
al. 1983;Nozakietal.2002). As it has been demonstrated that
secretin receptor mRNA expression decreases with age, it is
especially low, for example, in the amygdala and hippocam-
pus, by the age of 60 days (Tay et al. 2004).
The lateral habenular nucleus projects to the midbrain
dopaminergic systems and may be involved in reward-
seeking behaviors (Maia 2009). The lateral hypothalamic
and perifornical areas participate in several functions like the
sleep–wake and food intake regulation and regulation of the
body fluid homeostasis as well as in depression, anxiety, and
reward (Johnson and Thunhorst 1997; Valassi et al. 2008;
Chung et al. 2011; Kitka et al. 2011). Thus, secretin may be
associated with all of these roles.
Finally, it was concluded that the secretin receptors show a
more wide distribution in the brain than it was known before.
Our present and previous data (Heinzlmann et al. 2012)
obtained by radioactive in situ hybridization are semiquanti-
tatively illustrated and summarized in Fig. 4and Table 1,
respectively. The newly identified secretin receptor mRNA-
expressing areas are partly related to functions of secretin
previously accepted but also raise the possibility that secretin
may be related with new functions.
Acknowledgments We are grateful to Mrs. Anna Takács and Judit
Kerti for their excellent technical assistance. This work was supported by
ETT grant 495/09 to ZE Tóth and by the Department of Human
Morphology and Developmental Biology, Semmelweis University.
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