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THE JOURNAL OF COMPARATIVE NEUROLOGY 381:461–472 (1997)
Ontogeny of Somatostatin Binding Sites
in Respiratory Nuclei of the Human
Brainstem
VALÉRIE CARPENTIER,1 HUBERT VAUDRY,1 ERIC MALLET,2 JEAN TAYOT,3
ANNIE LAQUERRIÈRE,1,3 AND PHILIPPE LEROUX1*
1European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular
and Molecular Neuroendocrinology, INSERM U413, UA CNRS, University of Rouen,
76821 Mont-Saint-Aignan
2Service de Pédiatrie, Centre Hospitalier et Universitaire Charles Nicolle,
76031 Rouen, France
3Service de Neuropathologie, Centre Hospitalier et Universitaire Charles Nicolle,
76031 Rouen, France
ABSTRACT
The ontogeny of somatostatin binding sites was studied in 16 respiratory nuclei of the
human brainstem, from 19 postconceptional weeks to 6 months postnatal, by quantitative
autoradiography using [125I-Tyr0,DTrp8]S14 as a radioligand. In the early gestational stages
(19–21 postconceptional weeks), moderate to high concentrations of [125I-Tyr0,DTrp8]S14
binding sites were found in all nuclei, the highest density being measured in the locus
coeruleus. From 19 weeks of fetal life to 6 months postnatal, a decrease in the density of
labeling was observed in all nuclei. The most dramatic reduction in site density (80–90%) was
found in the ventral part of the nucleus medullae oblongata lateralis and in the nucleus
paragigantocellularis lateralis. A 70–80% decrease was detected in the dorsal part of the
nucleus tractus solitarius, the nucleus nervi hypoglossi, the ventral part of the nucleus
medullae oblongatae centralis, the nucleus ambiguus, the nucleus paragigantocellularis
dorsalis, and the nucleus gigantocellularis, and a 60–70% decrease in the nucleus parabrachialis medialis, the ventrolateral and ventromedial parts of the nucleus tractus solitarius, and
the nucleus praepositus hypoglossi. A 50–60% decrease was observed in the caudal part of the
nucleus tractus solitarius, the nucleus dorsalis motorius nervi vagi, and the nucleus
parabrachialis lateralis, whereas in the nucleus locus coeruleus, the concentration of
recognition sites decreased by only 30%. The profiles of the decrease in site density differed in
the various structures. In the majority of the nuclei, a gradual diminution of binding density
was observed either throughout the developmental period studied or mainly during fetal life.
Conversely, in two nuclei, i.e., the nucleus parabrachialis lateralis and the locus coeruleus, an
abrupt decrease occurred around birth. The differential decrease in the density of somatostatin binding sites observed in respiratory nuclei during development, together with the
observation that microinjection of somatostatin in some of these nuclei causes ventilatory
depression and apnea, strongly suggests that the somatostatinergic systems of the human
brainstem are involved in the maturation of the respiratory control. J. Comp. Neurol.
381:461–472, 1997. r 1997 Wiley-Liss, Inc.
Indexing terms: somatostatin receptors; quantitative autoradiography; medulla oblongata; pons;
ontogenesis
In humans, the maturation of the respiratory control
takes place during the fetal and postnatal period (Jansen
and Chernick, 1983, for review). Although spontaneous
breathing movements occur during fetal life, the mechanisms of regulation of intrauterine breathing activity in
the human fetus are unknown. In premature and full-term
infants, the various circuits that control respiration exhibit different patterns of maturation. Although the venti-
r 1997 WILEY-LISS, INC.
Contract grant sponsor: Institut National de la Santé et de la Recherche
Médicale (INSERM); Contract grant number: U413; Contract grant sponsor: Conseil Régional de Haute-Normandie.
*Correspondence to: Dr. P. Leroux, European Institute for Peptide
Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-SaintAignan, France. E-mail: philippe.leroux@univ.roven.fr
Received 7 May 1996; Revised 25 November 1996; Accepted 12 January
1997
462
latory response to hypercapnia and the strength of the
Hering-Breuer deflation reflex (increased inspiratory activity in response to lung deflation) increase during postnatal
life, the strength of the Hering-Breuer inflation reflex
(inhibition of inspiration in response to lung distension) is
stronger in preterm babies than in term newborns (Bodegard et al.,1969; Bodegard and Schwieler, 1971; Jansen
and Chernick, 1983, for review). In addition, a transient
response to hypoxia (hyperventilation followed by paradoxical hypoventilation) is observed in preterm babies (Jansen
and Chernick, 1983, for review). Finally, apneas are more
frequent in preterm than in full-term newborns, and the
frequency of apneic spells decreases during fetal life
(Curzi-Dascalova and Christova-Guéorguiéva, 1983;
Jansen and Chernick, 1983; Poets et al., 1994).
Anatomical and pharmacological studies have shown
that somatostatin may be an important regulator of respiratory activity. Somatostatin-producing neurons have been
visualized in various nuclei of the human brainstem
involved in the control of breathing. In particular, somatostatin-immunoreactive perikarya and fibers are abundant
in the nucleus (N.) ambiguus and the N. gigantocellularis
of the adult medulla (Bouras et al., 1987). In the infant
brainstem, somatostatin-containing cell bodies are also
present in the N. paragigantocellularis lateralis, the N.
praepositus hypoglossi, and the N. dorsalis motorius nervi
vagi (Chigr et al., 1989). In situ hybridization studies have
shown the expression of the somatostatin gene in the N.
tractus solitarius (Mengod et al., 1992), a major site of
cardiorespiratory reflex integration. Microinjection of somatostatin into the N. paragigantocellularis lateralis and
the N. reticularis lateralis causes ventilatory depression
and apnea in both rats (Chen et al., 1990; Chen et al., 1991)
and cats (Yamamoto et al., 1988). In human subjects,
intravenous injection of somatostatin induces inhibition of
the ventilatory response to hypoxia (Maxwell et al., 1986;
Filuk et al., 1988).
Five somatostatin receptor (sstr) genes have been cloned
(Yamada et al., 1992a; Yamada et al., 1992b; Yamada et al.,
1993) and their binding properties have been studied in
transfected cells (Patel and Srikant, 1994). Somatostatin
binding sites are widely expressed in the human brainstem (Reubi et al., 1986; Chigr et al., 1992; Carpentier et
al., 1996a; Carpentier et al., 1996b). In particular, high
concentrations of [125I-Tyr0,DTrp8]S14 binding sites have
been detected in various nuclei of the brainstem implicated in the regulation of the respiratory activity, such as
the N. dorsalis motorius nervi vagi, the N. tractus solitarius, and the N. parabrachialis (Carpentier et al., 1996a;
Carpentier et al., 1996b). The density of binding sites in
these nuclei is generally much higher in fetuses than in
adults (Carpentier et al., 1996a; Carpentier et al., 1996b),
suggesting the involvement of somatostatin in the maturation of respiratory centers of the human brainstem.
The aim of the present study was to determine the
ontogeny of somatostatin binding sites in respiratory
nuclei of the human brainstem, to investigate the possible
involvement of somatostatin in the development of central
respiratory control. The study was conducted by quantitative in vitro autoradiography in 8 fetuses and 14 infants
from 19 gestational weeks to 6 months postnatal, using a
radioligand that exhibits a high affinity for sstr2–5 and a
much lower affinity for sstr1 (Patel and Srikant, 1994).
V. CARPENTIER ET AL.
TABLE 1. Clinical Characteristics of Individuals1
Cases
Age
Sex
PMD
Cause of death
19 PC weeks
21 PC weeks
24 PC weeks
25.5 PC weeks
28 PC weeks
30 PC weeks
M
F
M
M
M
F
,12
4
,24
,24
23
22
VII
38 PC weeks
M
31
VIII
IX
X
XI
40 PC weeks
1 PN day
2 PN days
3 PN days
M
F
F
M
19
21
22
13
XII
XIII
9 PN days
13 PN days
M
F
6
22
Therapeutic abortion for Down’s syndrome
Spontaneous abortion; twin pregnancy
Spontaneous abortion; twin pregnancy
Premature rupture of membranes
Abruptio placentae
Anorectal malformation; antenetal peritonitis (meconial ileus)
Spontaneous expulsion of a non malformed
fetus; rupture of uterus following an
automobile accident
Fatal outcome during labour
Left diaphragmatic hernia
Acute purulent meningitis
Congenital cardiopathy (aortic stenosis);
heart failure
Acute meningitis
Acute respiratory failure; pericardiac
hematoma and ascitis (premature
delivery at 34 PC weeks)
Neonatal hepatitis
Congenital cardiopathy (abnormal pulmonary venous return)
Hepatic deficiency (premature infant born
at 29 PC weeks)
Cot death (bronchiolitis with severe inflammatory process affecting the larynx, trachea, bronchia and bronchioles)
Hyperpyretic gastroenteritis with serofibrinous pericardritis; pulmonary apoplexy
Cot death (diffuse pulmonary oedema and
massive bronchial aspiration of gastric
products)
Cot death (laryngotracheitis associated
with severe pulmonary oedema)
Stifled by bedding
Dehydration
I
II
III
IV
V
VI
XIV
XV
2 PN weeks
4 PN weeks
M
F
23
14
XVI
7 PN weeks
M
11
XVII
11 PN weeks
M
24
XVIII
15 PN weeks
M
4
XIX
17 PN weeks
M
22
XX
17 PN weeks
M
9
XXI
XXII
23 PN weeks
26 PN weeks
M
F
17
20
1PC,
postconceptional; PN, postnatal; PMD, postmortem interval (hours).
MATERIALS AND METHODS
Tissue preparation
Brainstems from 22 fetuses and infants were obtained at
the time of autopsy. The brains did not show any abnormality under macroscopic examination, and the postmortem
delay did not exceed 31 hours. None of the infants died
from sudden infant death syndrome (SIDS). The characteristics of each individual, including age, sex, postmortem
delay, and cause of death are summarized in Table 1. The
tissues were frozen in isopentane at 230°C without fixation and stored at 270°C. Each brainstem was sliced at 20
µm, in the frontal plane, from the rostral edge of the pons
to the C1 level of the cervical spinal cord, in a cryomicrotome at 215°C (Frigocut 2700, Reichert-Jung, Nussloch,
Germany). The sections were thaw-mounted on gelatinchrome alun-coated slides, dehydrated overnight under
vacuum at 4°C and kept at 270°C until use. For each
individual, three series of consecutive sections were collected every 200 µm.
Reagents
Synthetic somatostatin was provided by Dr. D. Djian
(Sanofi-Winthrop, Gentilly, France). [Tyr0,DTrp8]S14 was
synthesized by Dr. D.H. Coy (New Orleans, LA). Aprotinin
was from Hoechst Laboratories (Puteaux, France). Bovine
serum albumin (BSA; fraction V) was purchased from
Boehringer Mannheim (Meylan, France). Guanosine 58triphosphate (GTP) and bacitracin were obtained from
Sigma (St Louis, MO).
Autoradiographic procedure
Three micrograms of [Tyr0,DTrp8]S14 were radioiodinated by the lactoperoxidase technique as previously de-
ONTOGENY OF SOMATOSTATIN RECEPTORS IN BRAINSTEM
scribed (Laquerrière et al., 1989). The iodinated peptide
was purified by reversed phase high-performance liquid
chromatography on a Zorbax C-18 column (25 3 0.4 cm,
Merck, Darmstadt, Germany), using a mobile phase consisting of a gradient of acetonitrile in triethylammonium
phosphate buffer (pH 3). Monoiodinated [Tyr0,DTrp8]S14
eluted at 26% acetonitrile. The specific radioactivity of the
radioligand was approximately 2,000 Ci/mmol.
Tissue sections were preincubated for 30 minutes at
room temperature in 50 mM Tris buffer (pH 7.4) containing 5 mM MgCl2, 32 mM sucrose, 0.1% BSA (buffer A) in
the presence of 10-6 M GTP to dissociate endogenous
somatostatin from its receptors (Leroux et al., 1988). After
two rapid rinses in buffer A, a series of sections was
incubated with 20 pM of [125I-Tyr0,DTrp8]S14 for 2 hours at
room temperature, in buffer A supplemented with 0.4%
BSA, 5 µg/ml bacitracin, and 100 KIU/ml aprotinin. To
visualize nonspecific binding, a second series of sections
was incubated with the radioligand in the presence of 1 µM
somatostatin-14. The tissue slices were washed three
times for 5-minute periods at 0°C in buffer A without
sucrose. The sections were dried under a cold airstream,
apposed onto Hyperfilm-3H (Amersham, Les Ulis, France)
for 1 week. The films were developed for 2 minutes in
Kodak D19 developer and fixed for 10 minutes in Kodak
AL4 fixative solution. After exposure, the tissue sections
were stained with cresyl violet for microscopic determination of anatomical structures.
Acetylcholinesterase staining
To visualize brainstem nuclei, a third series of slices
adjacent to those used for autoradiography was stained for
acetylcholinesterase according to Paxinos and Watson
(1986). The sections were incubated for 15 hours in 50 mM
sodium acetate buffer (pH 5.0) containing 4 mM CuSO4, 16
mM glycine, 4 mM S-acetylthiocholine iodide, and 86 µM
ethopropazine. Then, the slices were rinsed with distilled
water and developed for 1 minute in an aqueous solution of
1% sodium sulphide (pH 7.5). After a mechanical rinse in
water, tissue slices were fixed in 4% paraformaldehyde in
0.1 M phosphate buffer (pH 7.4) for 5 minutes and allowed
to dry. Finally, the sections were dehydrated in two baths
of ethanol, cleared in cyclohexane, and mounted under
coverslips.
Autoradiographic quantification
Each film was calibrated with a series of brain paste
sections containing known concentrations of radioactivity.
The brain paste was composed of 40% rat brain, 40% tissue
embedding medium (Jung, Postfach, Germany), and 20%
aqueous solution of [125I-Tyr0,DTrp8]S14. The gray levels of
the autoradiograms were measured and compared with
those of the brain paste standards, by means of a BIO-500
image analysis system (Biocom, Les Ulis, France). The
density of binding sites was expressed as femtomoles of
sites per milligram of wet tissue as previously described
(Leroux et al., 1991).
The nomenclature of the brainstem nuclei was based on
the atlas of Olszewski and Baxter (1982). Identification of
acetylcholinesterase-positive areas was achieved according to Mizukawa et al. (1986). The density of somatostatin
binding sites was measured on the left and right hemisections on 200 µm-distant slices on the entire rostrocaudal
length of 16 nuclei known to participate in the control of
463
breathing. The density of binding sites in each nucleus was
calculated as the mean (6 SEM) of all measurements.
RESULTS
The autoradiographic localization and quantification of
somatostatin binding sites were performed in 8 fetuses, 2
premature infants, and 12 full-term infants. The distribution of the binding sites in the medulla oblongata of a
23-week-old infant is illustrated in Figure 1A. Incubation
of tissue slices with 1 µM somatostatin showed that nonspecific binding was uniform over the tissue sections (Fig. 1B).
Depending on the intensity of labeling, the nonspecific
binding level varied from 4 to 82% of total binding, in the
different respiratory nuclei studied. Acetylcholinesterase
staining made it possible to identify brainstem nuclei
macroscopically (Fig. 1C), whereas microscopic determination of anatomical structures was performed on cresyl
violet-stained sections (Fig. 1D). The anatomical localization of the brainstem nuclei in fetuses was similar to that
in adults, as described in the atlas of Olszewski and Baxter
(1982), thus allowing the measurement of somatostatin
binding sites in accurately identified structures (Fig. 2).
The distribution of labeling in two representative fetuses
aged 19 and 38 gestational weeks (individuals I and VII,
respectively) and in a 15-week-old infant (individual XVIII)
is illustrated at the level of the pons (Fig. 3A–C), the
inferior olive (Fig. 3D–F), and the basal medulla (Fig. 3G–I).
Substantial concentrations of somatostatin binding sites
were found in all respiratory nuclei studied in the fetuses
(Table 2). At the earlier gestational stages (19–21 weeks), a
very high density of sites (60 fmol/mg wet tissue) was
detected in the N. locus coeruleus. High concentrations of
binding sites (40–60 fmol/mg wet tissue) were measured in
the N. gigantocellularis, the nuclei paragigantocellularis
lateralis and dorsalis, the ventrolateral and ventromedial
parts of the N. tractus solitarius, the N. parabrachialis
medialis, and the ventral aspects of the nuclei medullae
oblongatae centralis and lateralis. Moderate densities of
sites (40 fmol/mg wet tissue) were found in the caudal and
dorsal aspects of the N. tractus solitarius, the N. praepositus hypoglossi, the N. parabrachialis medialis, the N. nervi
hypoglossi, the N. ambiguus, and the N. dorsalis motorius
nervi vagi (Table 2).
In all the respiratory nuclei studied, the density of
somatostatin recognition sites decreased during development, but the amplitude and kinetics of the changes in
receptor binding markedly differed in the various nuclei
(Table 2, Fig. 4). The reduction in binding site density
reached 80–90% in the ventral subnucleus of the N.
medullae oblongata lateralis and in the N. paragigantocellularis lateralis (Fig. 4F,K). The density of sites decreased
by 70–80% in the dorsal part of the N. tractus solitarius
(Fig. 4B), the N. nervi hypoglossi (Fig. 4E), the ventral
subnucleus of the N. medullae oblongata centralis (Fig.
4G), the N. ambiguus (Fig. 4I), the N. paragigantocellularis dorsalis (Fig. 4J), and the N. gigantocellularis (Fig.
4L). The concentration of binding sites decreased by
60–70% in the ventrolateral and ventromedial parts of the
N. tractus solitarius (Fig. 4C,D), the N. parabrachialis
medialis (Fig. 4N), and the N. praepositus hypoglossi (Fig.
4M). Concurrently, the concentration of sites diminished
by 50–60% in the caudal part of the N. tractus solitarius
(Fig. 4A), the N. dorsalis motorius nervi vagi (Fig. 4H), and
the N. parabrachialis lateralis (Fig. 4O) and by 30% only in
the N. locus coeruleus (Fig. 4P).
464
V. CARPENTIER ET AL.
Fig. 1. Illustration of the autoradiographic localization of [125ITyr0,DTrp8]S14 binding sites in the medulla oblongata of an infant at
23 postnatal weeks (case XXI in Table 1). A: Total binding of
[125I-Tyr0,DTrp8]S14; B: Nonspecific binding of the radioligand in the
presence of 1 µM somatostatin; C: Acetylcholinesterase histochemical
staining; D: Cresyl violet staining. Am, nucleus (N.) ambiguus;
D.mo.X, N. dorsalis motorius nervi vagi; N.XII, N. nervi hypoglossi;
Ol.i.pr, N. olivaris inferior principalis; T.sol, tractus solitarius. Scale
bar 5 0.5 cm.
The kinetics of the changes in the density of somatostatin binding sites followed three different patterns. In the
dorsal part of the N. tractus solitarius, the N. dorsalis
motorius nervi vagi, and the N. praepositus hypoglossi, the
density of sites decreased gradually from the 19th gestational week to the 6th month postnatal, although the
decrease was more slow during the postnatal period (Fig.
4B,H,M). In a second group of structures comprising the
ventrolateral and ventromedial parts of the N. tractus
solitarius (Fig. 4C,D), the N. ambiguus (Fig. 4I), the
ventral subnuclei of the N. medullae oblongatae centralis
and lateralis (Fig. 4F,G), the N. gigantocellularis (Fig. 4L),
the nuclei paragigantocellularis dorsalis and lateralis
(Fig. 4J,K), and the N. parabrachialis medialis (Fig. 4N),
the density of somatostatin binding sites markedly decreased during fetal development and remained relatively
stable after birth. In a third group of structures, including
the N. parabrachialis lateralis (Fig. 4O) and the N. locus
coeruleus (Fig. 4P), the concentration of recognition sites
did not vary appreciably during the fetal period but
decreased abruptly in the perinatal period.
In general, the densities of somatostatin binding sites in
respiratory nuclei from individuals of the same age were
similar. However, in newborns aged from 1 day to 2 weeks,
substantial interindividual variations of labeling intensity
were observed in all the nuclei studied (Table 2, Fig. 4). In
almost all areas, the density of sites measured in the two
fetuses that were almost at term (aged 38 and 40 gestational weeks) were higher than those measured in the
neonates.
DISCUSSION
Methodological considerations
Previous studies have shown that storage of rat brains
at 4°C for up to 24 hours has no effect on the distribution
and concentration of somatostatin binding sites (Beal et
al., 1986; Reubi et al., 1986). Similarly, the postmortem
interval does not affect the density of somatostatin recognition sites in the human hypothalamus and brainstem
(Najimi et al., 1991; Chigr et al., 1992). Thus, the postmor-
ONTOGENY OF SOMATOSTATIN RECEPTORS IN BRAINSTEM
465
Fig. 2. Acetylcholinesterase staining (A,C,E) and corresponding
autoradiographs showing the total binding of [125I-Tyr0,DTrp8]S14
(B,D,F) obtained from adjacent sections of the brainstem of a 28
gestational week-old fetus, at the level of the pons (A,D), the rostral
(B,E), and the caudal medulla oblongata (C,F). Am, N. ambiguus; Coe,
locus coeruleus; D.mo.X, N. dorsalis motorius nervi vagi; N.XII, N.
nervi hypoglossi; Pb.l, N. parabrachialis lateralis; Sol.c, N. tractus
solitarius, pars caudalis. Scale bar 5 0.1 cm.
tem interval of the individuals studied in the present work
(#31 hours) should not have provoked major alterations of
the distribution or concentration of receptors in the brain-
stem nuclei. In fact, we did not observe any correlation
between the density of somatostatin binding sites and the
postmortem delay of the specimens. The present study was
466
Fig. 3. Autoradiographic localization of [125I-Tyr0,DTrp8]S14 binding sites at the level of the pons (A–C), the inferior olive (D–F), and the
basal medulla (G–I) in a fetus at 19 gestational weeks (A,D,G; case I in
Table 1), a fetus at 38 gestational weeks (B,E,H; case VII in Table 1)
and a 15-week-old infant (C,F,I, case XVIII in Table 1). Nonspecific
binding obtained in the presence of 1 µM somatostatin was low and
uniform in all three individuals (J–L). Cn.v, N. medullae oblongatae
V. CARPENTIER ET AL.
centralis, subnucleus ventralis; Coe, locus coeruleus; D.mo.X, N.
dorsalis motorius nervi vagi; Gc, N. gigantocellularis; L.v, N. medullae
oblongatae lateralis, subnucleus ventralis; Pb.l, N. parabrachialis
lateralis; Prp, N. praepositus hypoglossi; Sol.c, N. tractus solitarius,
pars caudalis; Sol.d, N. tractus solitarius, pars dorsalis. Scale bar 5
0.25 cm.
ONTOGENY OF SOMATOSTATIN RECEPTORS IN BRAINSTEM
467
TABLE 2. Density of [125I-Tyr0,DTrp8 ]S14 Binding Sites (fmol/mg wet tissue) in Different Nuclei of Individuals at Various Stages of Development1
I (19 PC weeks)
II (21 PC weeks)
III (24 PC weeks)
IV (25.5 PC weeks)
V (28 PC weeks)
VI (30 PC weeks)
VII (38 PC weeks)
VIII (40 PC weeks)
IX (1 PN day)
X (2 PN days)
XI (3 PN days)
XII (9 PN days)
XIII (13 PN days)
XIV (2 PN weeks)
XV (4 PN weeks)
XVI (7 PN weeks)
XVII (11 PN weeks)
XVIII (15 PN weeks)
XIX (17 PN weeks)
XX (17 PN weeks)
XXI (23 PN weeks)
XXII (26 PN weeks)
I (19 PC weeks)
II (21 PC weeks)
III (24 PC weeks)
IV (25.5 PC weeks)
V (28 PC weeks)
VI (30 PC weeks)
VII (38 PC weeks)
VIII (40 PC weeks)
IX (1 PN day)
X (2 PN days)
XI (3 PN days)
XII (9 PN days)
XIII (13 PN days)
XIV (2 PN weeks)
XV (4 PN weeks)
XVI (7 PN weeks)
XVII (11 PN weeks)
XVIII (15 PN weeks)
XIX (17 PN weeks)
XX (17 PN weeks)
XXI (23 PN weeks)
XXII (26 PN weeks)
Am
Cn.v
Coe
D.mo.X
Gc
L.v
N.XII
Pb.l
N.D.
31.2 6 2.3 (5)
37.2 6 7.6 (6)
20.2 6 3.0 (7)
12.1 6 1.4 (10)
26.6 6 2.1 (8)
25.8 6 1.6 (12)
19.3 6 1.4 (18)
3.6 6 0.9 (9)
5.5 6 1.4 (13)
10.5 6 0.8 (13)
15.8 6 1.2 (13)
7.2 6 0.7 (13)
15.9 6 1.1 (9)
11.0 6 0.9 (15)
23.3 6 1.1 (12)
8.4 6 0.8 (15)
9.2 6 0.4 (20)
11.5 6 0.6 (18)
11.2 6 0.5 (16)
10.2 6 0.7 (20)
3.3 6 0.7 (21)
36.2 6 1.7 (28)
46.6 6 3.1 (20)
24.8 6 2.6 (11)
31.7 6 1.3 (28)
19.1 6 1.4 (29)
28.8 6 1.6 (36)
13.5 6 0.6 (51)
25.0 6 1.0 (27)
3.2 6 0.5 (26)
15.2 6 1.5 (25)
14.4 6 0.7 (22)
N.D.
10.8 6 0.6 (28)
18.2 6 0.5 (24)
7.9 6 0.4 (30)
25.8 6 0.7 (31)
8.1 6 0.6 (33)
6.7 6 0.3 (38)
12.4 6 0.4 (35)
9.0 6 0.4 (32)
10.6 6 0.3 (32)
1.9 6 0.6 (32)
74.7 6 5.5 (27)
91.2 6 4.8 (22)
77.9 6 3.9 (26)
87.1 6 3.9 (36)
83.1 6 2.5 (22)
94.5 6 5.9 (17)
71.7 6 3.8 (33)
79.8 6 2.5 (21)
46.9 6 1.9 (17)
68.3 6 4.4 (16)
80.7 6 4.0 (25)
N.D.
49.5 6 1.7 (18)
70.7 6 1.7 (21)
39.4 6 1.2 (24)
57.7 6 0.8 (29)
65.9 6 3.5 (38)
61.0 6 3.7 (40)
77.2 6 5.4 (35)
51.7 6 2.4 (46)
64.2 6 2.1 (29)
17.8 6 2.4 (45)
33.8 6 2.5 (18)
31.1 6 2.1 (25)
28.5 6 4.1 (14)
21.6 6 1.5 (28)
24.5 6 1.5 (30)
22.0 6 1.9 (28)
27.9 6 1.3 (35)
27.8 6 1.1 (40)
7.7 6 0.5 (31)
24.2 6 1.7 (48)
27.4 6 1.0 (27)
33.1 6 2.5 (7)
19.6 6 0.8 (33)
27.3 6 1.0 (15)
19.4 6 0.7 (29)
26.8 6 1.0 (26)
22.3 6 1.3 (42)
15.1 6 0.9 (51)
23.0 6 0.8 (36)
17.3 6 0.8 (35)
14.0 6 0.5 (21)
10.6 6 1.1 (34)
44.9 6 2.1 (26)
35.5 6 2.1 (28)
39.8 6 2.1 (28)
33.4 6 2.1 (34)
18.7 6 1.1 (32)
25.8 6 1.5 (28)
14.0 6 1.2 (26)
20.6 6 1.1 (39)
5.0 6 0.5 (37)
4.3 6 0.8 (43)
12.4 6 0.6 (45)
19.1 6 0.8 (41)
10.6 6 0.5 (36)
18.4 6 0.5 (32)
9.4 6 0.7 (39)
20.9 6 0.8 (31)
6.5 6 0.5 (39)
9.0 6 0.6 (48)
9.4 6 0.7 (44)
8.5 6 0.6 (41)
10.2 6 0.4 (47)
1.4 6 0.7 (30)
49.0 6 3.3 (24)
68.6 6 5.5 (10)
28.0 6 2.7 (13)
32.7 6 1.0 (23)
22.3 6 1.6 (21)
29.9 6 1.4 (19)
18.3 6 1.3 (12)
22.3 6 1.2 (17)
5.4 6 0.5 (24)
22.5 6 2.1 (26)
15.4 6 0.6 (20)
N.D.
12.2 6 0.7 (27)
14.8 6 0.6 (21)
8.7 6 0.5 (29)
22.3 6 0.6 (27)
9.0 6 0.5 (26)
4.8 6 0.3 (22)
11.5 6 0.5 (29)
9.7 6 0.4 (29)
9.4 6 0.5 (23)
2.7 6 0.6 (18)
29.9 6 2.5 (22)
34.6 6 2.6 (20)
15.9 6 3.0 (8)
18.1 6 2.0 (27)
16.6 6 1.4 (28)
23.2 6 1.6 (32)
18.7 6 1.7 (25)
28.5 6 1.1 (26)
3.8 6 0.5 (26)
15.2 6 1.5 (30)
19.7 6 1.0 (20)
24.0 (1)
13.1 6 0.7 (28)
17.9 6 1.0 (23)
9.8 6 0.7 (30)
25.1 6 0.6 (33)
8.4 6 0.7 (33)
6.6 6 0.4 (37)
12.1 6 0.5 (34)
9.5 6 0.5 (31)
10.7 6 0.5 (32)
2.7 6 0.6 (32)
N.D.
31.2 6 3.5 (8)
31.6 6 6.6 (4)
24.7 6 2.1 (16)
25.0 6 1.6 (8)
31.8 6 2.0 (6)
18.3 6 1.6 (17)
34.1 6 1.9 (17)
12.6 6 1.4 (8)
24.6 6 1.5 (16)
19.7 6 1.2 (13)
28.2 6 2.4 (8)
12.6 6 1.1 (23)
19.0 6 0.8 (9)
14.0 6 0.8 (21)
26.2 6 1.5 (10)
14.3 6 1.0 (22)
13.4 6 0.8 (25)
17.1 6 0.7 (17)
16.4 6 1.2 (20)
12.9 6 1.2 (7)
0.1 6 0.7 (21)
Pb.m
Pg.d
Pg.l
Prp
Sol.c
Sol.d
Sol.vl
Sol.vm
46.7 6 1.1 (4)
57.7 6 3.5 (4)
42.8 6 3.6 (7)
27.9 6 2.3 (9)
34.1 6 1.2 (13)
33.1 6 2.7 (9)
26.8 6 1.2 (20)
35.0 6 1.8 (13)
12.1 6 1.5 (7)
21.7 6 2.1 (8)
28.7 6 2.0 (10)
N.D.
17.5 6 1.1 (13)
29.5 6 1.4 (10)
14.2 6 1.3 (10)
25.6 6 1.0 (9)
22.2 6 1.1 (17)
14.7 6 1.1 (16)
15.7 6 0.9 (16)
14.1 6 0.7 (18)
17.1 6 1.0 (26)
7.8 6 1.2 (18)
44.5 6 2.8 (15)
36.3 6 2.4 (16)
42.7 6 3.3 (18)
32.3 6 2.3 (17)
16.0 6 0.7 (17)
25.8 6 1.6 (14)
14.1 6 1.4 (14)
21.7 6 1.1 (23)
4.5 6 0.8 (16)
3.7 6 0.8 (20)
12.3 6 0.8 (28)
16.9 6 0.6 (30)
10.9 6 0.7 (23)
17.2 6 0.8 (22)
10.6 6 1.0 (19)
22.2 6 0.6 (18)
8.2 6 0.8 (23)
9.7 6 0.5 (32)
9.3 6 1.0 (23)
6.7 6 0.8 (25)
11.2 6 0.5 (30)
1.3 6 0.7 (29)
52.6 6 3.0 (14)
35.0 6 1.3 (17)
36.1 6 3.2 (10)
31.8 6 2.0 (17)
20.4 6 1.4 (17)
26.3 6 1.7 (14)
19.4 6 1.6 (12)
19.1 6 1.1 (24)
6.4 6 0.8 (18)
9.5 6 0.4 (21)
13.2 6 0.8 (29)
16.9 6 0.6 (28)
10.3 6 0.8 (23)
15.2 6 0.6 (23)
9.6 6 1.0 (18)
20.8 6 0.8 (17)
7.8 6 0.4 (23)
9.1 6 0.5 (32)
11.0 6 0.8 (26)
7.5 6 0.4 (25)
10.3 6 0.5 (28)
2.6 6 0.7 (25)
36.6 6 2.4 (20)
33.0 6 1.9 (20)
27.6 6 2.8 (18)
18.7 6 2.7 (18)
17.6 6 0.9 (22)
23.9 6 1.4 (16)
22.7 6 1.3 (19)
28.7 6 2.4 (27)
8.7 6 1.1 (18)
10.2 6 1.2 (19)
19.7 6 0.9 (29)
18.1 6 1.1 (23)
15.4 6 0.4 (24)
17.4 6 0.7 (22)
17.2 6 0.8 (28)
20.5 6 0.8 (18)
10.2 6 0.7 (23)
13.6 6 1.2 (36)
12.4 6 0.6 (32)
9.9 6 0.6 (27)
14.0 6 0.4 (33)
3.9 6 0.7 (25)
33.4 6 2.7 (15)
28.2 6 3.7 (15)
N.D.
27.8 6 1.2 (15)
25.8 6 2.3 (6)
36.4 6 2.4 (16)
26.7 6 1.0 (32)
35.0 6 1.9 (31)
5.5 6 0.6 (18)
29.2 6 2.3 (27)
24.4 6 1.2 (14)
31.8 6 1.2 (8)
14.4 6 0.9 (14)
24.0 6 0.6 (14)
12.4 6 0.7 (20)
26.5 6 1.6 (10)
22.3 6 1.2 (15)
13.5 6 1.0 (19)
24.2 6 1.1 (12)
19.2 6 0.9 (8)
18.5 6 0.9 (23)
15.7 6 1.8 (12)
45.5 6 3.6 (8)
33.2 6 3.0 (7)
32.1 6 3.6 (11)
23.5 6 1.7 (20)
20.5 6 1.2 (26)
18.5 6 1.4 (27)
31.4 6 1.5 (21)
28.2 6 1.2 (26)
5.1 6 0.4 (14)
21.9 6 4.3 (9)
21.8 6 1.6 (18)
22.9 6 1.2 (12)
14.9 6 1.1 (23)
18.9 6 0.8 (11)
19.8 6 0.6 (19)
21.3 6 0.8 (24)
14.2 6 0.8 (23)
13.3 6 0.8 (28)
17.0 6 0.5 (29)
14.1 6 0.5 (28)
12.2 6 0.5 (22)
6.2 6 0.9 (23)
47.0 6 3.5 (8)
48.1 6 5.7 (9)
32.1 6 5.7 (9)
33.6 6 2.0 (20)
18.6 6 1.0 (23)
25.5 6 2.0 (25)
23.6 6 1.2 (24)
28.7 6 1.3 (27)
5.2 6 0.5 (14)
20.8 6 2.3 (10)
15.1 6 0.6 (19)
25.4 6 1.0 (15)
11.2 6 0.8 (22)
22.9 6 0.6 (15)
15.5 6 0.7 (19)
26.3 6 0.7 (25)
13.9 6 1.1 (20)
14.3 6 0.8 (28)
16.9 6 0.8 (31)
13.5 6 0.4 (28)
15.9 6 0.9 (22)
5.8 6 0.7 (24)
52.4 6 3.1 (7)
37.6 6 3.8 (9)
29.6 6 3.2 (9)
33.4 6 2.5 (20)
22.6 6 1.5 (24)
29.1 6 2.1 (25)
27.1 6 1.4 (21)
28.7 6 1.3 (27)
5.4 6 0.6 (14)
20.2 6 1.8 (10)
18.5 6 0.9 (19)
30.0 6 1.3 (14)
12.7 6 0.9 (22)
26.0 6 0.8 (12)
16.9 6 0.6 (20)
27.6 6 0.7 (25)
13.5 6 0.8 (20)
17.6 6 1.6 (28)
18.6 6 0.6 (31)
15.4 6 0.6 (28)
16.5 6 0.7 (22)
5.5 6 0.9 (23)
1Values in parentheses indicate the number of measurements. PC, postconceptional; PN, postnatal; N.D., not determined. Cases XIII and XVI were prematures born at 34 and 29
weeks, respectively.
performed on a population of infants who died from
various causes and whose brainstems did not show any
abnormality under macroscopic examination. No obvious
differences were noticed between individuals who died
accidentally (case XXI) or after a prolonged reanimation
period (cases XV and XVIII), suggesting that the disease or
the reanimation period had no apparent effect on the
density of somatostatin receptors.
Cresyl violet staining did not delineate macroscopically
several brainstem nuclei that are either too close to each
other or too small, such as the N. ambiguus and the N.
dorsalis motorius nervi vagi. We have thus used acetylcholinesterase staining to identify and delineate these structures unequivocally.
The recent molecular cloning of somatostatin receptors
has revealed the existence of five structurally related
receptor subtypes that are expressed in a tissue specific
manner (Yamada et al., 1992a; Yamada et al., 1992b;
Yamada et al., 1993; Raulf et al., 1994). Pharmacological
characterization of the recombinant receptors indicates
that somatostatin-28 (S28) is the only molecule exhibiting
high affinity for all five sstrs, whereas D-Trp8-substituted
analogues possess high affinity for sstr2–5 and a lower
affinity for sstr1 (Raynor et al., 1993a; Raynor et al.,
1993b; Patel and Srikant, 1994). Because the S28 tracer
[125I-Leu8,DTrp22,Tyr25]S28 produces high nonspecific bind-
ing on human brain tissue (Laquerrière et al., 1992), in the
present study we have used [125I-Tyr0,DTrp8]S14 as a
radioligand and therefore all sstrs but sstr1 were detected.
The nonspecific binding was uniform within each brainstem N. studied but slightly varied between individuals.
The specific binding ranged from 18 to 96% in the various
nuclei from the different individuals. The observation that
the densities of somatostatin binding sites were similar in
all individuals of the same age (except for newborn infants)
suggests that the measurement of the binding site density
was reliable. In support of this hypothesis, we recently
observed a strong correlation between the densities of
somatostatin recognition sites in 96 structures of the
brainstems from three human fetuses, by using the same
experimental conditions as in the present study (Carpentier et al., 1996b).
Developmental changes in the density
of somatostatin binding sites
The present study has shown that high densities of
somatostatin binding sites are present in discrete nuclei of
the human brainstem as early as 19–21 weeks of gestation
and that the intensity of labeling decreases between
midgestation and the postneonatal period. The amplitude
of the decrease in the different nuclei studied was variable.
Fig. 4. Variation of the density of [125I-Tyr0,DTrp8]S14 binding
sites during development in 16 areas of the brainstem involved in
respiratory regulation. Individuals were plotted according to their age
expressed as postconceptional weeks. The densities of binding sites
were measured in the medulla and pons of 8 fetuses (filled circles) aged
from 19 to 40 gestational weeks, 2 premature infants (open circles)
born at 29 and 34 gestational weeks who died 7 weeks and 13 days
after birth, respectively, and 12 full-term infants (open triangles) aged
from 1 day to 26 weeks. Am, N. ambiguus; Cn.v, N. medullae ob-
longatae centralis, subnucleus ventralis; Coe, N. locus coeruleus;
D.mo.X, N. dorsalis motorius nervi vagi; Gc, N. gigantocellularis; L.v,
N. medullae oblongatae lateralis, subnucleus ventralis; N.XII, N.
nervi hypoglossi; Pb.l, N. parabrachialis lateralis; Pb.m, N. parabrachialis medialis; Pg.d, N. paragigantocellularis dorsalis; Pg.l, N.
paragigantocellularis lateralis; Prp, N. praepositus hypoglossi; Sol.c,
N. tractus solitarius, pars caudalis; Sol.d, N. tractus solitarius, pars
dorsalis; Sol.vl, N. tractus solitarius, pars ventrolateralis; Sol.vm, N.
tractus solitarius, pars ventromedialis.
ONTOGENY OF SOMATOSTATIN RECEPTORS IN BRAINSTEM
Figure 4
For example, the density of binding sites dropped by
80–90% in the ventral subnucleus of the N. medullae
oblongatae lateralis and the N. paragigantocellularis lat-
469
(Continued.)
eralis but diminished by only 30% in the N. locus coeruleus. In most brainstem nuclei studied, the density of
somatostatin binding sites was approximately twofold
470
higher in 4- to 6-month old babies (this study) than in
adults (Carpentier et al., 1996a). In the N. locus coeruleus,
the density of sites was fourfold higher in infants (cases
XVIII–XXI) than in adults (Carpentier et al., 1996a). In
contrast, the levels of labeling in the N. nervi hypoglossi
were similar in infants and in adults. The use of a
nonselective somatostatin receptor radioligand made it
possible to determine the overall evolution of receptor
density (except sstr1). It is, therefore, possible that the
variations of the binding intensity reflect more complex
evolution of the various sstr subtypes. However, because of
the lack of selective ligands for human sstr on the one hand
(Patel and Srikant, 1994) and to the impossibility to collect
large enough series of sections from each nucleus for
competition studies on the other hand, it was not possible
to identify precisely which sstr subtype(s) contributed to
the binding of [125I-Tyr0,DTrp8]S14.
The physiological processes controlling the evolution of
the concentration of somatostatin receptors in the human
brain are currently unknown. The decline of binding site
density in the brainstem during the second half of gestation and the postnatal period could be assigned to various
causes, such as a decrease in receptor gene expression, a
reduction of the density of neurons resulting from gliogenesis and/or neuronal death, an involution of pre- or postsynaptic neuronal arborizations bearing receptors, or a decrease in receptor affinity. We have previously shown that,
in the rat brain, the density of somatostatin binding sites
undergoes a significant decrease at the time of birth and
after imposed weaning, suggesting that stressful stimuli
may exert a negative influence on the expression of the
receptors (Gonzalez et al., 1989). It is tempting to speculate that the abrupt decrease in the concentration of
somatostatin binding sites observed in the N. parabrachialis lateralis and the N. locus coeruleus during the perinatal
period may be ascribed to neural and/or endocrine regulation of receptor gene expression. It has previously been
shown that somatostatin inhibits the expression of its own
receptors in anterior pituitary cells (Draznin et al., 1985;
Mentlein et al., 1989), pancreatic acinar cells (Viguerie et
al., 1987), and anterior pituitary tumor cells (Reisine and
Axelrod, 1983; Heisler and Srikant, 1985). Therefore, the
decrease in the density of somatostatin binding sites
observed in the human brainstem nuclei during development might also result from downregulation of the receptors by endogenous somatostatin. A diminution of the
density of neurons actually occurs in all nuclei of the
human brainstem during the second half of gestation
together with the growth of the neuropil (Sidman and
Rakic, 1982). However, the decrease in neuron density is
gradual and thus cannot account for the abrupt decrease
in somatostatin binding site concentration observed in
several structures during the postnatal period. Important
variations in the number of dendritic spines have been
reported in the human medulla oblongata during the
perinatal period (Quattrochi et al., 1985; Takashima and
Becker, 1986; Takashima and Becker, 1991). In particular,
in the ventrolateral medulla, the number of spines augments during gestation and rapidly diminishes after birth
(Takashima and Becker, 1986; Takashima and Becker,
1991), suggesting that the decrease in binding site density
observed in the N. paragigantocellularis lateralis and the
ventral subnucleus of the N. medullae oblongatae lateralis
can be accounted for, at least in part, by the decline in
dendritic spine density during the postnatal period. Previ-
V. CARPENTIER ET AL.
ous studies performed in rats (Gonzalez et al., 1989;
Gonzalez et al., 1990) or human brain tissues (Laquerrière
et al., 1992) have shown that the affinity of somatostatin
receptors is remarkably constant during development; it is
thus unlikely that the decline in [125I-Tyr0,DTrp8]S14
binding could be ascribed to a decrease in receptor affinity.
Localization of somatostatin binding
sites and somatostatin immunoreactivity
in the infant brainstem
To our knowledge, the distribution of somatostatin in the
brainstem of the human fetus has never been determined.
In the brain of infants and adults, the occurrence of
somatostatin-immunoreactive neurons has been reported
in numerous brainstem nuclei, particularly in structures
involved in respiratory control (Bouras et al., 1987; Chigr
et al., 1989). In infants, the distribution of somatostatin
binding sites (this study) largely overlaps the localization
of somatostatin-containing fibers (Chigr et al., 1989). In
particular, the high intensity of labeling observed in the N.
locus coeruleus, the N. dorsalis motorius nervi vagi, and
the N. tractus solitarius coincides with the presence of an
abundant network of somatostatin-immunoreactive fibers
in these structures (Chigr et al., 1989). The occurrence of
both somatostatin-immunoreactive fibers and somatostatin binding sites in brainstem nuclei involved in the
command of respiratory rhythmicity, such as the N. tractus solitarius, the N. parabrachialis, and the N. paragigantocellularis lateralis, provides strong evidence for a physiological role of somatostatin in the control of breathing.
Possible involvement of somatostatin
receptors in the development
of respiratory control
The present study has shown a marked decrease in the
density of somatostatin binding sites in brainstem areas
that contain chemosensitive neurons, such as the N.
paragigantocellularis lateralis and the ventral aspect of
the N. medullae oblongatae lateralis (Coates et al., 1993;
Sun and Reis, 1994; Bianchi et al., 1995; Sun and Reis,
1995). Studies performed in rats and cats have shown that
microinjection of somatostatin in these two structures
induces apnea (Yamamoto et al., 1988; Chen et al., 1990;
Chen et al., 1991). In humans, the ventilatory response to
hypercapnia and hypoxia undergoes profound modifications during the fetal and postnatal periods. In particular,
hyperventilation in response to hypercapnia increases
during development, whereas the response to hypoxia in
preterm babies is characterized by a transient hyperventilation followed by a paradoxical hypoventilation (Jansen
and Chernick, 1983; Bonora et al., 1994). These observations suggest that the decrease in the density of somatostatin binding sites in the N. paragigantocellularis lateralis
and in the ventral aspect of the N. medullae oblongatae
lateralis may contribute to the maturation of the chemoreflexes, possibly by modulating the responses of central
chemosensitive neurons located in these two nuclei.
We have also observed an important decrease of the
density of somatostatin binding sites in several nuclei that
contain rhythmic discharging neurons, namely, in the N.
tractus solitarius, the N. paragigantocellularis lateralis,
and the ventral aspect of the N. medullae oblongatae
lateralis (Bystrzycka and Nail, 1985; Morin-Surun and
Denavit-Saubié, 1989; Ezure, 1990; Bongiani et al., 1993;
ONTOGENY OF SOMATOSTATIN RECEPTORS IN BRAINSTEM
Bianchi et al., 1995; Richerson et al.,1995). Studies conducted in rats (Chen et al., 1990; Chen et al., 1991) or cats
(Yamamoto et al., 1988) have shown that microinjection of
somatostatin in these nuclei causes ventilatory depression
and apnea. These data suggest that the decrease in the
density of somatostatin binding sites detected in respiratory nuclei could be responsible, at least in part, for the
decrease in the frequency of apneas observed in human
during the postnatal period (Curzi-Dascalova and Christova-Guéorguiéva, 1983; Jansen and Chernick, 1983; Poets et al., 1994).
CONCLUSION
The present study has shown that the concentration of
somatostatin binding sites decreases in respiratory nuclei
of the human brainstem during fetal and postnatal development. In particular, a marked diminution of the density
of somatostatin recognition sites occurs in several nuclei at
the onset of extrauterine breathing. The high levels of
somatostatin binding sites present in the respiratory
nuclei of the fetus brainstem may account for the paradoxical depression of ventilation during hypoxia and for the
increased frequency of apneic spells observed in the preterm infants. Although many risk factors appear to be
associated with SIDS, there is increasing evidence that
discrete modifications of the dynamic equilibrium of reciprocal communication between respiratory nuclei is the
cause of fatal apnea (O’Kusky and Norman, 1995). In this
context, it is conceivable that an impaired maturation of
somatostatinergic transmission in respiratory centers may
predispose infants to SIDS. Therefore, the present study
will serve as a basis to investigate whether babies who
died of SIDS exhibit abnormal expression of somatostatin
receptors in respiratory nuclei.
ACKNOWLEDGMENTS
This work was supported by the Institut National de la
Santé et de la Recherche Médicale (INSERM U413) and
the Conseil Régional de Haute-Normandie. V.C. was a
recipient of a fellowship from the Association ‘‘Naı̂tre et
Vivre Haute-Normandie.’’
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