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MICROSCOPY RESEARCH AND TECHNIQUE 46:24–47 (1999)
Distribution of the Catecholaminergic Neurons in the Central
Nervous System of Human Embryos and Fetuses
CATHERINE VERNEY*
INSERM U.106, Bâtiment Pédiatrie, Hôpital Salpêtrière, 75651-Paris Cedex 13, France
KEY WORDS
development; dopamine; cerebral cortex; immunocytochemistry; noradrenaline;
tyrosine-hydroxylase
ABSTRACT
The catecholaminergic cell groups in the human brain, denominated from A1 to
A17, display some striking anatomical differences with those described in the rodent. These
differences are essentially observed in the extent of the dopaminergic neurons and especially their
axonal fields in the telencephalon. Immunocytochemistry for tyrosine-hydroxylase and dopamine-ßhydroxylase allowed the visualization of the precocious human catecholaminergic groups as early as
4.5 postovulatory weeks. Maps of tyrosine-hydroxylase positive neurons generated in the different
rhombomeres, midbrain, and prosomeres are shown following the prosomeric model introduced by
Puelles and Rubenstein [(1993) Trends Neurosci. 16:472–476]. Such a description is convenient to
compare catecholaminergic systems in different mammalian species and provide clear anatomical
landmarks of the embryonic substantia nigra (midbrain and prosomeres 1 and 2), that are necessary
for transplantation of neural tissue in Parkinson’s disease. The development and early specification
of the dopaminergic neurons expressing calbindin D28K phenotype in the substantia nigra and in
the ventral tegmental area are described. The catecholaminergic axons enter the anlage of the
cerebral cortex just after the formation of the cortical plate, from 7 postovulatory weeks on. They
invade the subplate layer where they wait for 4 weeks before penetrating the cortical plate. At
midgestation, the different areas and layers of the frontal cerebral wall are invaded by the
catecholaminergic axons, before the layering of the cortex is completed, in a pattern of fiber
distribution similar to that described in the adult human brain. The early pattern of development of
the catecholamine systems appeared to be phylogenetically well preserved in mammals, but specific
features emerging during the differentiation period are unique to humans. Microsc. Res. Tech.
46:24–47, 1999. r 1999 Wiley-Liss, Inc.
INTRODUCTION
The discovery of the technique of histofluorescence of
catecholamines, more than 30 years ago allowed the
description of the different catecholaminergic (CA) cell
groups distributed along the caudorostral axis of the
CNS and innervating numerous areas and nuclei (Fig.
1) (Björklund and Lindvall, 1984; Dahlström and Fuxe,
1964; Falck et al., 1962; Lindvall and Björklund, 1978,
1983). The central dopamine-, noradrenaline-, and
adrenaline-containing neurons have a neuromodulatory function on various neuronal fields involved in
autonomic, motor, or cognitive functions.
The CA neuronal groups emerge and develop axonal
fibers very early during development (Lauder and
Bloom, 1974; Olson et al., 1973; Olson and Seiger, 1972;
Specht et al., 1981; Verney et al., 1982, 1984). This led
to the hypothesis of a regulatory or trophic role of the
precocious CA fibers on their target neurons in the
cerebral cortex during development in the rat or cat
(Bear and Singer, 1986; Blue and Parnavelas, 1982;
Kasamatsu and Pettigrew, 1976; Kasamatsu et al.,
1981). For humans, a developmental dopaminergic
(DA) dysfunction has been suggested in neurological
and psychiatric disorders such as Parkinson’s disease
and schizophrenia (Deutch, 1993; Grace, 1993; Lewis,
1997; Weinberger et al., 1988). The recent advent of
r 1999 WILEY-LISS, INC.
transplantation strategy in the treatment of Parkinson’s disease makes it essential to study the DA neurons of embryonic human specimens appropriate for
grafting (Lindvall et al., 1992). Phylogenetic studies in
mammals have shown striking particularities of the DA
systems in primates vs. rodents in the distribution of
cell bodies and in the extension of the axonal fibers
especially in the telencephalon (Berger et al., 1991;
Dubach, 1994; Kitahama et al.,1994; Panayotacopoulou
and Swaab, 1993; Tillet, 1994). As most of the descriptive and developmental studies on the CA systems have
been performed in the rat, it becomes essential to get
more information in primates and especially in humans.
The first section of this account presents an anatomical overview of the CA neuronal groups in the adult
human brain compared to that described in monkey
and rodent brain, with special emphasis on the CA
innervation of the cerebral cortex. The second section
reports our data on the development of these cell groups
and of their efferences entering the cerebral cortex
Contract grant sponsor: INSERM; Contract grant sponsor: ECC; Contract
grant number:CI1 CT90 O848.
*Correspondence to: Catherine Verney, INSERM U.106, Bâtiment Pédiatrie,
Hôpital Salpêtrière, 47 Bd de l’Hôpital, 75651-Paris, France. E-mail:
cverney@infobiogen.fr
Received 10 October 1998; accepted in revised form 4 January 1999
Fig. 1. Schematic drawing of the main CA groups named A1 to A15
and C1, C2 distributed along the caudorostral axis of the adult human
brain and their predominant efferences (for details see Table 1).
Dopaminergic groups are located in the midbrain and forebrain
whereas noradrenergic and adrenergic are distributed in the hindbrain The scheme ‘‘development’’ presents the prenatal ages (in weeks
or days) when the first neurons of the locus coeruleus (LC) and
substantia nigra (SN) are generated in the human, monkey and rat.
The fetal age at which the first DA and noradrenergic axons are
visualized as they penetrate the cortical anlage are indicated for the
human, monkey, and rat.
26
C. VERNEY
during the first half of gestation in humans. We compare our data to those obtained by other teams and,
since the literature on these topics is abundant, we will
cite many review papers that the reader is referred to
for more details.
DISTRIBUTION OF THE CENTRAL
CATECHOLAMINE NEURONS IN THE ADULT
HUMAN BRAIN
Methodological Remarks
The pioneer histofluorescence technique of CA has
now been replaced by immunocytochemical labeling,
which allows the study of CA neurons in experimental
animals as well as in human postmortem specimens
(Dahlström and Fuxe, 1964; Falck et al., 1962; Hökfelt
et al., 1974, 1984). The use of antisera directed against
the enzymes of the synthetic pathway of CA, as well as
against dopamine and noradrenaline themselves or
their transporters, allow us to discriminate between
the dopaminergic, noradrenergic, and adrenergic neuronal groups (Fig. 2A) (Blackely et al., 1994; Geffard et al.,
1984; Giros et al., 1992; Hökfelt et al., 1974, 1984;
Smeets and Steinbusch, 1990; Smiley et al., 1992;
Verney et al., 1990). The first enzyme is tyrosinehydroxylase (TH), the rate-limiting enzyme, which
converts tyrosine to DOPA, which is then converted to
dopamine by a nonspecific decarboxylase, the L-aromatic aminoacid-decarboxylase (AADC). DOPA has
been considered as a precursor for dopamine but its
recent immunocytochemical visualization in different
cell populations even in humans suggests that it could
also have a neurotransmitter function (Ikemoto et al.,
1997; Kitahama et al. 1988; Smeets and Steinbusch,
1990). TH-immunoreactivity is the phenotypic marker
most commonly used for simultaneous characterization
of dopaminergic, noradrenergic, and adrenergic cell
bodies (Fig. 2A). Dopamine-ß-hydroxylase (DBH)immunoreactivity is specific to noradrenergic and adrenergic neurons and phenylethanolamineN-methyl-transferase (PNMT)-immunoreactivity is present only in
adrenergic neurons (Kitahama et al., 1994). But, there
have been puzzling results showing the presence of the
amine without the synthetic enzyme or vice versa
(Foster, 1994; Kitahama et al., 1994; Smeets and Reiner,
1994; Zecevic and Verney, 1995). For example, THimmunoreactivity could label cell populations in which
no other CA traits have been identified as in the
coliculli during mammal development (Jeager and Joh,
1983; Puelles and Verney, 1998; Zecevic and Verney,
1995). Also, most antisera directed against TH label
preferentially DA rather than noradrenergic axons in
the cerebral cortex during development (Verney et al.,
1982, 1993) and in adult primates (Noack and Lewis,
1992; Gaspar et al., 1989). In situ hybridization technique allows to ascertain the presence of messengers
for TH in cells where the protein is detected and,
interestingly, human TH exists as at least four isoforms
generated by alternative splicing of mRNA (Alterio et
al.,1998; Dumas et al., 1996; Grima et al., 1987; Kaneda
et al., 1987; Lewis et al., 1993). Another specific method
used to visualize CA fibers and terminals is based on
their selective uptake in slices maintained in vitro. This
method allowed the distinction of one CA axonal terminal field from another (Berger et al., 1986, 1988).
Distribution of the Central
Catecholamine-Containing Cell Groups
In their first description of the central CA systems,
Dahlström and Fuxe (1964) recognized 12 groups of
fluorescent neurons in the rat brain, which they labeled
A1 to A12, from caudal to rostral. Immunocytochemical
techniques allowed Hökfelt and his colleagues (1984) to
confirm the presence of these noradrenaline- and dopamine-cell groups and also to identify additional groups,
A13 to A17. PNMT-immunocytochemistry allowed the
visualization of the adrenergic neuronal groups in the
brainstem of the rat named C1-C2 (Hökfelt et al., 1974)
(Figs. 1, 2A). Those nomenclatures are largely adopted
for all mammals including humans. Most of the CA
groups (except the adrenergic cells) in human adult,
contain melanin pigment (Bogerts, 1981; Gaspar et al.,
1983; Saper and Petito, 1982) and could thus be recognized without immunohistochemical detection. Table 1
summarizes the locations of the CA neuronal groups
detected in human (Dubach, 1994; Kitahama et al.,
1994; Puelles and Verney, 1998; Tillet, 1994). Such a
description is schematic since the CA neurons of each
group are usually not confined to known cytoarchitectural boundaries, but intermingle with other cell types
especially in humans (Kitahama et al., 1994; Pearson et
al., 1990).
Rhombencephalon. The noradrenergic neurons of
A1-A2 groups associated with the adrenergic neurons of
C1-C2 are scattered within a continuous longitudinal
motor related band extending from the ventrolateral
medulla (A1-C1) to the dorsomedial medulla (A2-C2)
(Arango et al., 1988; Halliday et al., 1988; Kitahama et
al,. 1988, 1994, 1996; Pearson et al., 1983, 1990; Robert
et al., 1984). A3 group is not mentioned in Table 1 since
its existence is questionable as no immunocytochemical
studies mention it in the adult mammalian brain
(Hökfelt et al., 1984; Smeets and Reiner, 1994). In
humans, the pigmented nucleus of the cerebellar tegmentum (A4) is located near the locus coeruleus (A6),
which extends dorsal to the locus subcoeruleus (A7).
The rostral noradrenergic neurons of the A5 group are
distributed near the Kölliker-Fuse nucleus ventral to
the brachium conjunctivum whereas the caudal neurons of this group are near the lateral paragigantocellular nucleus in the medulla oblongata (Kemper et al.,
1987; Kitahama et al,. 1994, 1996; Nobin and Björklund, 1973; Pearson et al., 1983, 1990; Robert et al.,
1984).
Mesencephalon. The DA groups, the retrorubral
area A8, the substantia nigra A9, and the ventral
tegmental area A10 are often called ‘‘midbrain’’ groups
whereas in mammals including humans, the A9-A10
groups extend in the diencephalic segment, rostral to
the third nerve root (Gaspar et al., 1983; German et al.,
1983; Halliday and Tork, 1986; Hirsch et al., 1992;
Kitahama et al., 1994; Pearson et al., 1983, 1990; Van
Domburg and Donkelaar, 1991). In humans, the A8 DA
group is dispersed in the tegmentum caudal to the red
nucleus, and caudodorsal to the substantia nigra. The
substantia nigra is composed of the pars compacta
containing DA neurons densely packed in an horizontal
band (A9), which penetrates ventrally the pars reticulata comprising GABA containing neurons (Oertel et
al., 1982) (Fig. 3). The lateral extension of the DA
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
27
Fig. 2. A: A schema of the synthetic pathway of catecholamines:
dopamine, noradrenaline and adrenaline. B: Topological model of the
longitudinal and neuromeric domains of the embryonic brain, illustrating the relative positions of the diverse TH-IR populations (modified
with permission from Puelles and Verney, 1998). The longitudinal
zones, floor (FP), basal (BP), alar (AP), and roof plates (RP) are
indicated at the left side and the neuromeric elements are shown at
the bottom; larger morphological units are identified at the top. The
circle drawn in p6 represents the eye stalk containg A17 group. The
different TH-IR areas indicated by dark grey represent the permanent
populations whereas the light grey areas show transient ones. Terminology by Dahlström and Fuxe (1964) is followed to a large extent,
with a few exceptions (see Puelles and Verney, 1998). DR, dorsal raphe
nucleus; hb, habenula; HL, lateral hypothalamic cell group; lc, locus
coeruleus; lsc, locus subcoeruleus; mam, mammillary group; RM,
retromammillary area; PR, pontine raphe; tect, tectum.
neurons forms the substantia nigra pars lateralis. In
their atlas of the human brain, Olszewski and Baxter
(1954) divided the pars compacta into three horizontal
ventrodorsal bands called alpha, beta, and gamma. The
gamma band corresponds to the dorsal horizontal DA
neuronal population, coexpressing calbindin D28K phe-
notype and projecting rather to limbic and cortical
areas. The ventral DA neurons are less numerous to
express calbindin D28K and rather project to motorrelated structures (Gaspar et al., 1992, 1993; McRitchie
et al., 1996). More recent studies considered that the
DA neurons of the dorsal band of the substantia nigra
28
C. VERNEY
TABLE 1. Central catecholamine (CA)-containing neuronal groups in humans*
CA
A
Group
C1
Brain segment
Main localization in human brain
Caudal rhombencephalon
Ventrolateral reticular area (ventral to the ambiguus nucleus) (Arango et al., 1988; Halliday
et al., 1988; Kitahama et al., 1985; 1988; 1994, 1996; Pearson et al., 1983; 1990; Robert et
al., 1984)
A
C2
Caudal rhombencephalon
Substantia gelatinosa subnucleus and nucleus of the solitary tract (Arango et al., 1988; Halliday et al., 1988; Kitahama et al., 1985; 1988; 1994; 1996; Pearson et al., 1983; 1990;
Robert et al., 1984)
NA
A1
Caudal rhombencephalon
Ventrolateral reticular area (including the ambiguus nucleus) (Arango et al., 1988; Halliday
et al., 1988; Kitahama et al., 1988; 1994, 1996; Pearson et al., 1983; 1990; Robert et al.,
1984)
NA
A2
Caudal rhombencephalon
Nucleus of the solitary tract, dorsal nucleus of nerve X and adjacent reticular parvocellular
area (Arango et al., 1988; Halliday et al., 1988; Kitahama et al., 1988; 1994; 1996; Pearson
et al., 1983; 1990; Robert et al., 1984)
NA
A4
Rostral rhombencephalon
Pigmented nucleus of the cerebellar tegmentum (Kitahama et al., 1994; Nobin and Björklund,
1973; Pearson et al., 1983)
NA
A5
Rhombencephalon
Kölliker-Fuse nucleus and lateral paragigantocellular nucleus (Kitahama et al., 1994; Nobin
and Björklund, 1973; Pearson et al., 1983; 1990)
NA
A6
Rostral rhombencephalon
Locus coeruleus (Pearson et al., 1983; 1990; Kemper et al., 1987; Kitahama et al., 1994; 1996;
Nobin and Bjöklund, 1973; Pearson et al., 1983; 1990; Robert et al., 1984)
NA
A7
Rostral rhombencephalon
Locus subcoeruleus (A6 for some authors) & (Pearson et al., 1983; 1990; Kemper et al., 1987;
Kitahama et al., 1994; 1996; Pearson et al., 1983; 1990; Robert et al., 1984)
DA
A8
Mesencephalon-isthmus
Tegmental field caudal to the red nucleus and dorsal to A9 (Hirsch et al., 1992; Halliday and
Tork, 1986; Kitahama et al., 1994; Pearson et al.; 1983; 1990; Van Domburg and Donkelaar,
1991)
DA
A9
Mesencephalon-diencephalon Substantia nigra pars compacta (Gaspar et al., 1983; German et al., 1983; Halliday and Tork,
1986; Hirsch et al., 1992; Kitahama et al., 1994; Pearson et al., 1983; 1990; Van Domburg
and Donkelaar, 1991)
DA
A10
Mesencephalon-diencephalon Ventral tegmental area (the paranigral and parabrachialis pigmentosus nuclei, the central
and rostral linearis nuclei of raphe, the interfascicularis and the Edinger-Westphal nuclei.
around the mammillary nuclei) (German et al., 1983; Halliday and Tork, 1986; Hirsch et al.,
1992; Kitahama et al., 1994; Pearson et al., 1983; 1990; Puelles and Verney, 1998; Su et al.,
1987; Van Domburg and Donkelaar, 1991)
DA
A11
Caudal diencephalon
The periaqueductal grey—along the caudal part of the IIIrd ventricle, (Pearson et al., 1990;
Su et al., 1987; Tillet et al., 1994)
DA
A12
Intermediate diencephalon
Tuberoinfundibular nucleus (Pearson et al., 1990, Spencer et al., 1985; Su et al., 1987; Tillet et
al., 1994)
DA
A13
Intermediate diencephalon
Dorsomedial hypothalamus and zona incerta (Pearson et al., 1990, Spencer et al., 1985; Su et
al., 1987; Tillet et al., 1994)
DA
A14
Rostral diencephalon
Periventricular area of the IIIrd ventricle lateral anterior hypothalamic area (Pearson et al.,
1990, Spencer et al., 1985; Su et al., 1987; Tillet et al., 1994)
DA
A15
Rostral diencephalon
Supraoptic nucleus—paraventricular hypothalamic nucleus (Li et al., 1988; Pearson et al.,
1990; Panayotacopoulou et Swaab, 1993; Su et al., 1987; Tillet et al., 1994)
DA
A16
Telencephalon
Periglomerular neurons of the olfactory bulb; (Halasz and Shepherd, 1983; Smith et al., 1991)
TH-IR neurons Telencephalon
Basal forebrain near the olfactory tract, in the ventral striatum and in the basal nucleus of
Meynert (Dubach, 1987; Gaspar et al., 1985; Köhler et al., 1983; Gouras, 1992). The cerebral cortex (Gaspar et al., 1987; Hornung et al., 1989; Kuljis et al., 1989, Lewis et al., 1991;
Trottier et al., 1989).
DA
A17
Amacrine cells in inner nuclear layer of the retina (Frederick et al., 1982; Nguyen-Legros et
al., 1992)
*A: adrenaline, NA: noradrenaline, DA: dopamine. The nomenclature is adapted from Dahlström and Fuxe (1964) and Hökfelt et al., (1974). TH-IR: tyrosine
hydroxylase immunoreactive neurons.
could correspond or overlap those of the parabrachialis
pigmentosus nucleus, which extend more medially and
are included in the ventral tegmental area (A10 group)
(Kitahama et al., 1994; McRitchie et al.,1996; Porrino
and Goldman-Rakic, 1982). The ventral tegmental area
is composed of DA neurons dispersed in the reticular
formation adjacent to the nucleus interpeduncularis,
the red nucleus, and the substantia nigra (Fig. 3). It
comprises the nuclei paranigralis and parabrachialis
pigmentosus, the central and rostral linearis nuclei of
the raphe, the interfascicularis and the EdingerWestphal nuclei. The TH-IR neurons located around
the mammillary nuclei in humans are included in the
ventral tegmental area as they have a similar pattern
of development to the DA neurons of this group (Pearson et al., 1990; Puelles and Verney, 1998; Su et al.,
1987). Conversely, DA neurons of the periaqueductal
gray, which have been included in the ventral tegmen-
tal area in most studies, are classified within A11 group
(Kitahama et al., 1994; Puelles and Verney, 1998;
Smeets and Reiner, 1994).
Most of these DA neurons of A8–A10 groups and of
subpopulations of A9 group (aforementioned) express
the calbindin D28K phenotype. The phenotypic expression of calbindin D28K within the DA neurons is
interesting since it defines a neuronal subpopulation
that appears to be more resistant to cell death induced
by Parkinson’s disease than the one containing only
dopamine (German et al., 1992; Hirsch et al., 1992;
Yamada et al., 1990; Yamada et al., 1990).
Diencephalon. The DA groups A11 to14 groups
spread within the diencephalon but also include some
midbrain neurons (Table 1) (Pearson et al., 1990;
Spencer et al., 1985; Su et al., 1987; Tillet, 1994). TH
positive DA neurons are distributed in a dorsal band
extending along the ventricle from the mesencephalon
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
29
Fig. 3. Semischematic drawings of a half of the human midbrain
stained for TH-immunoreactivity. A: Section at the level of the red
nucleus. B: Section at the level of the decussation of the superior
cerebellar peduncle. The limit between the DA neurons of the parabrachialis pigmentous nucleus (pbp), which is considered as a part of the
ventral tegmental area (vta), and those of the dorsal part of the
substantia nigra pars compacta (snc) is not clear (short arrows). The
ventral clustered DA neurons of the pars compacta send dendrites and
intermingle with the neurons of the pars reticulata (snr) (long arrow).
The ventral tegmental area (vta) comprises DA neurons in the
paranigralis nucleus (pn) and the pbp, the central and rostral linearis
nuclei of the raphe (cli, rli). IIIn, oculomotor nerve; aq, aqueduc; ip,
interpeduncularis nucleus; lm, medial lemiscus; mlf, medial longitudinal fasciculus; rn, red nucleus; pag, periaqueductal grey; scp, superior
cerebellar peduncle; snl, substantia nigra pars lateralis. Reprinted
from Kitahama K, Nagatsu I, Pearson J. 1994. Catecholamine systems
in mammalian midbrain and hindbrain: theme and variation. In:
Smeets WJAJ, Reiner A, editors. Phylogeny and development of
catecholamine systems in the CNS of vertebrates. Cambridge: Cambridge University Press. p 183–206. with permission .
to the diencephalon: as mentioned above, we classified
the DA neurons of the periaqueductal gray as the
caudal part of A11 group. The A11 group in humans
comprises the DA neurons along the border of the IIIrd
ventricle in the caudal diencephalon, which are not
clearly separated from those of A13 group located more
rostrally.
Numerous TH-positive neurons are observed within
the paraventricular and supraoptic and hypothalamic
nuclei in humans, the A15 group, whereas only a few
scattered neurons are detected in this latter group in
rodents (Li et al., 1988; Pearson et al., 1990; Panayotacopoulou et Swaab, 1993; Tillet, 1994).
Telencephalon. Several studies have reported the
presence of TH-IR cells in the telencephalon of human
and non-human primates whereas they are not detected in the rat, excepted during development (see
review in Dubach, 1994). In humans, they consist of
heterogeneous TH-IR cell populations mostly dispersed
in the basal forebrain near the olfactory tract and the
ventral striatum (Gaspar et al., 1985; Köhler et al.,
1983), spreading caudally in the basal nucleus of Mey-
nert (Dubach, 1994; Gouras et al., 1992). Some TH-IR
neurons coexpressing the dopamine transporter DAT
were mentioned recently in the monkey striatum. These
presumably DA neurons also coexpress GABA as mentioned for TH positive neurons described in the primate
cerebral cortex (Betarbet et al., 1997; Trottier et al.,
1989). Indeed, in primates, TH containing neurons
visualized by immunocytochemistry and by in situ
hybridization of RNA probe constitute less than 0.1% of
the cortical neuronal population (Gaspar et al., 1987;
Hornung et al., 1989; Kuljis et al., 1989; Lewis et al.,
1987, 1991; Trottier et al., 1989). These TH positive
cortical neurons present a characteristic laminar and
regional distribution and are restricted to association
cortices (prefrontal or limbic related areas), rather than
to primary cortical areas (Gaspar et al., 1987; Lewis et
al., 1991). As for striatal neurons, they could be DA and
could also use GABA for non-aminergic neurotransmission (Trottier et al., 1989). But as these neurons are
lacking other CA traits, DOPA has been also suggested
as a possible neurotransmitter (Gaspar et al., 1987).
30
C. VERNEY
Noradrenergic and Dopaminergic Ascending
Efferent Fiber Systems to the Telencephalon
and Particularly the Cerebral Cortex
In mammals, the ascending noradrenergic axons
originate in the locus coeruleus (A6) and run dorsally in
the dorsal tegmental bundle. They assemble with the
DA efferences from the substantia nigra pars compacta
(A9) and the ventral tegmental area (A10) to constitute
the medial forebrain bundle that innervates the diencephalic and telencephalic areas (Lindvall and Björklund,
1978, 1983). The bulk of the DA axons goes to the basal
ganglia, and the CA fibers destined to the certebral
cortex enter the frontal pole from its rostroventral
aspect (Berger and Verney, 1984; Lindvall and Björklund, 1978, 1983).
The noradrenergic axons are widely distributed in all
layers and areas of the cerebral cortex in rodents and
primates. A slight regional difference is observed in the
pattern of fiber distribution in rodents (review in
Berger and Gaspar, 1994; Levitt and Moore, 1978;
Morrison et al., 1978), whereas a clear heterogeneity in
the distribution of these fibers is detected in primates.
Innervation is denser in the somatosensory and motor
cortical areas and decreases caudally in the occipital
lobe and rostrally in the frontal lobe. In primates,
variations in the density of innervation are also observed across the different cortical layers (Berger and
Gaspar, 1994; Gaspar et al., 1989; Lewis and Morrison,
1989; Morrison et al., 1982).
The DA mesotelencephalic system in mammals refers
to the ascending projections from the A9–A10 cell
groups, which are segregated into two components: (1)
the nigrostriatal system that originates in the ventral
and lateral part of A9 and innervates the caudateputamen and globus pallidus (Gerfen, 1992; Graybiel,
1990; Haber and Groennewegen, 1990); (2) the mesocorticolimbic system originating in the dorsal and medial
A9 and the adjacent A10 and innervating the cerebral
cortex , the olfactory bulb, the anterior olfactory nucleus,
the olfactory tubercle, the piriform cortex, the septal
area, the nucleus accumbens, and the amygdaloid
complex (Lindvall and Björklund, 1983). The DA innervation of the cerebral cortex is strikingly different
between primates and rodents. The major DA terminal
fields are restricted to frontal, cingulate, and entorhinal cortices in rodents, whereas DA innervation is
present in all cortical areas with major regional differences in density and laminar distribution in primates
(Berger et al., 1986, 1988, 1991; Berger and Gaspar,
1994; Gaspar et al., 1989; Lewis et al., 1987; Maeda et
al., 1995). In humans, the DA innervation is densest in
agranular cortices (motor area 4–6, cingulate area 24
and insula) and lowest in granular cortical areas (prefrontal area 9, parietal area 3b or visual area 17). In the
agranular cortices, TH-IR axons are present in all
layers with accumulations in patches in layer II and III,
whereas in other cortices such as the occipital cortex, a
bilaminar pattern of distribution in layer I and layers
V–VI is observed (Gaspar et al., 1982). This widespread
distribution of the DA fibers and teminals within the
human cerebral cortex is a major evolutionary specialization when compared to rodents.
DEVELOPMENT OF
CATECHOLAMINE-CONTAINING NEURONS
IN HUMAN EMBRYOS AND FETUSES
The pioneer Swedish teams have detected the presence of fluorescent monoaminergic cell bodies at 7
gestational weeks in humans (Olson et al., 1973) but
the distinct CA groups and axonal pathways have been
clearly described in 3–4-month-old fetuses and onwards
(Choi et al., 1975; Nobin and Björklund, 1973; Pearson
et al., 1980; Sailaja and Gopinath, 1994; Su et al.,
1987). At this latter developmental stage, fluorescent
CA fibers were observed penetrating the basal ganglia
and a few of them were seen in the cerebral cortex. THimmunolabeling could identify CA neurons in the sympathetic ganglia by 5 gestational weeks (Pickel et al.,
1980), and in the substantia nigra and locus coeruleus
by 9–10 gestational weeks (Pearson et al., 1980). In
Rhesus monkeys, the neurons of the locus coeruleus
and of the substantia nigra are generated between the
4th and 6th gestational week corresponding to the first
quarter of gestation (Levitt and Rakic, 1982) whereas
CA efferents towards the cortical anlage are currently
observed at the 10th gestational week (Berger et al.,
1992) (Fig. 1). In the rat, the CA neuronal groups are
generated during the second half of gestation, between
embryonic days 12 and 15 (Altman and Bayer, 1981;
Lauder and Bloom, 1974; Specht et al., 1981) and the
CA efferences to the cortex penetrate the frontal areas
at embryonic day 16 for the DA innervation and day 17
for the noradrenergic (Schlumpf et al., 1980; Verney et
al., 1982, 1984) (Fig. 1). Comparing the developmental
stages of the locus coeruleus and substantia nigra
neurons in rats and humans, O’Rahilly and collaborators (1987) suggested that embryonic days 13–15 in the
rat approximatively corresponded to Carnegie stages
15–18 (4.5 to 6 postovulatory weeks) in humans. Indeed, our results and those of other teams, show the
presence of TH immunoreactive CA groups during the
embryonic period in humans (Almqvist et al., 1996;
Freeman et al., 1991; Puelles and Verney, 1998; Ugrumov et al., 1996; Verney et al., 1991; Zecevic and Verney,
1995).
Specimens and Methods
We had access to specimens from 10 human embryos
that corresponded to 4.5 to 8 postovulatory weeks
(provided by Dr. Zecevic) and 10 fetuses aged from 10 to
24 weeks (O’Rahilly and Gardner, 1971; Puelles and
Verney, 1998; Verney et al., 1996; Zecevic and Verney,
1995). These specimens were obtained in Yugoslavia
and France from medically indicated or spontaneous
abortions following the recommendations of the French
(CCNESVS, 90 294) and Yugoslavian Ethical Committees. The embryonic specimens were obtained with no
postmortem delay, which gave an excellent preservation of the tissue. On the other hand, the fetal brains
were obtained with a postmortem delay ranged from 2
to 15 hours, which brought some variations in the
density of positive fibers detected in the fetal cerebral
cortex. Embryos or brain samples were fixed in 4%
paraformaldehyde, rinsed, frozen, and cut serially in
the frontal or sagittal planes. Groups of adjacent sections were immunostained with primary antisera
against TH (polyclonal and monoclonal antibodies)
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Fig. 4. Camera lucida mappings of sagittal sections of human
embryos. The TH-immunoreactive (IR) neurons are indicated by dots
and the interneuromeric boundaries by radial lines connecting the
ventricle (shaded in gray) with the brain surface. Microphotographs of
some regions of the histological sections drawn on these figures are
shown in Figure 5A,E for panel A and Figure 7A for panel B. A: Medial
level of the specimen at 4.5 postovulatory weeks (Carnegie stage 15).
Rostral is to the left, dorsal side is up. Cranial nerves or ganglia are
marked in Roman numbers. Rhombomeres or prosomeres are identified by Arabic numbers. TH-immunolabeling of the telencephalon,
midbrain and rostral brainstem is shown in Figure 5A and a high
magnification of the locus coeruleus area in Figure 5E. The main
TH-immunoreactivity is detected within the IIIrd cranial nerve and
root (III), and the rare TH-IR neurons, which correspond to the anlage
of the A9-A10 groups, are not present at this level. B: TH-IR elements
in medial sagittal sections of a 6-week-old specimen (stage 18). The
TH-IR neurons are mapped by dots roughly proportional to the
31
relative density. The main TH-IR neuronal groups are well defined in
the hindbrain, midbrain, and diencephalon and are identified with
conventional abbreviations (sn, lc, vta). The vta is shown at a higher
magnification in Figure 7A; Note that some labeled cells are detected
in the habenular area (hab) around the pineal stalk and in the inferior
colliculus (ci), while they have lost their transient immunoreactivity in
the superior colliculus. IV, trochlear nucleus and nerve; cb, cerebellar
primordium; cs, superior colliculus; dth, dorsal thalamus; lc, locus
coeruleus; mam, mammillary body and cell group; mes, mesencephalon; ob, olfactory bulb; p1-p6, prosomeres; pc, posterior commissure;
po, preoptic area; r1-r8, rhombomeres; rm, retromammillary area; sc,
spinal cord; sol, nucleus of the solitary tract; tel, telencephalon; tm,
tuberomammillary nucleus; tr, retroflex tract; vta, ventral tegmental
area; vth, ventral thalamus; zi, zona incerta. Reprinted from Puelles
L, Verney C. 1998. Early neuromeric distribution of tyrosineimmunoreactive neurons in human embryos. J Comp Neurol 394:283–
308, with permission.
32
C. VERNEY
(Vigny and Henry, 1981), DBH, PNMT, calbindin D28K
and calretinin, and gonadotropin-releasing hormone
(Puelles and Verney, 1998; Verney et al., 1991, 1992,
1993, 1996; Zecevic and Verney, 1995). For single
immunocytochemistry, we used the streptavidin-biotinperoxidase staining procedure while the double immunolabeling was accomplished either by the simultaneous visualization of immunofluorescent markers
obtained in different species (Verney et al., 1992, 1993)
or by a sequential double immunostaining (Verney et
al., 1996).
Embryonic Neuromeric Description of the TH-IR
Catecholaminergic Neuronal Groups in
Hindbrain, Midbrain, Diencephalon, and
Prosencephalon
The segmental organization of the vertebrate neural
tube, introduced by the anatomists at the turn of the
century, is largely accepted nowadays (see review of
Bergquist and Kallen, 1954; Vaage, 1969). Analysis of
expression of homeobox-containing genes has provided
new insights into the organization of the vertebrate
embryos revealing basic developmental units organized
in both longitudinal and transverse subdivisions. The
hindbrain is composed of 7–8 rhombomeres whose
boundaries are determined by fixed pattern of brain
stem motor nuclei and nerve roots (Lumsden and
Keynes, 1989). In accord with Puelles and Rubenstein
(1993), the forebrain (prosencephalon) includes the
diencephalon composed of three prosomeres, p1, p2, p3
and the secondary prosencephalon subdivided into three
additional segments p4, p5, p6 (Figs. 2B, 4, 5) (Bulfone
et al., 1993; Puelles and Rubenstein, 1993; Puelles,
1995; Shimamura et al., 1995).
In an embryo of 4.5 postovulatory weeks (Carnegie
stage 15), TH-immunoreactive (IR) cells are present in
all transverse sectors of the brain: prosomeres, midbrain, rhombomeres, and spinal cord (Figs. 2B, 5). The
abundance of TH-IR neurons suggests that these neurons could already exist in slighly younger specimens,
but the observed pattern is immature enough to support the assumption that most TH-IR neurons are
found close to their respective neuroepithelial source.
The CA neurons express TH-immunoreactivity as soon
as they leave the ventricular zone where they are
generated. Each segment shows a specific pattern, with
a dorsoventral topology of the TH-IR neurons distributed in the floorplate, basal plate, and alar plate as
described in detail in Puelles and Verney (1998).
Rhombomeres. The embryo of 4.5 postovulatory
weeks (Carnegie stage 15) displays TH-positive neurons of the presumable A1-C1 and A2-C2 groups distributed, respectively, in the basal and alar plates of
rhombomeres 6 (r6) and 7 (r7). Different TH-IR subpopulations are generated in the distinct rhombomeres
migrating radially within the segment where they are
generated with no clear-cut evidence for interneuro-
Fig. 5. Photomicrographs of sagittal TH-immunostained sections
of the specimen at 4.5 postovulatory weeks. Rhombomeric boundaries
are indicated by arrowheads at the limiting ventricular ridges. Rostral
is to the left, dorsal is side up. A: medial sagittal level shown in
drawing Figure 4A where TH-immunoreactivity is observed in the III
oculomotor neurons and rootlets. Numerous TH-IR neurons are
detected in the hypothalamic area (prosomeres, p3–4). A row of TH
positive cells is observed in the superior colliculus (cs). B,C: illustrate
the dorsolateral hindbrain with diverse, segmentally-restricted groupings of TH-IR neurons and fibers, Note changes in number and density
of positive cells across the boundaries of different rhombomeres.
D,E: Details of the locus coeruleus area on serial sagittal sections
visualized with DBH-immunocytochemistry (D) and TH-immunocytochemistry (E). Note the DBH-immunoreactivity of the trochlear nerve
fibers along their intraneural ventrodorsal course. For abbreviations
see Figure 4; V, trigeminal ganglion; VII, facial ganglion; VIII, acoustic
ganglion; IX, glossopharyngeal nerve root; X, pneumogastric ganglion;
XII, hypoglossal ganglion; rh, rhombencephalon. Scale bars ⫽ 100 µm
in A–C, 50 mm in D, E. Reproduced from Puelles L, Verney C. 1998.
Early neuromeric distribution of tyrosine-immunoreactive neurons in
human embryos. J Comp Neurol 394:283–308, with permission.
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Fig. 6. Sagittal section showing TH-IR elements in the hindbrain
at 6 postovulatory weeks (stage 18). The rhombomeric limits (indicated by arrowheads) are traced by reference to the whole section
series, cranial nerve roots, and nuclear formations as seen in adjacent
Nissl-stained sections. The caudal limit of the locus coeruleus (lc)
coincides with the r1/r2 boundary, while its rostral end seems to lie
caudal to the isthmus (is), below the A4 cell group and the cerebellum
(cb). The caudal A5 group lies in r6. The caudalmost hindbrain shows
33
the A1, A2 basal part—marked A2—and C1 basal cell groups, as well
as numerous alar TH-IR cells of conventional A2 within the solitary
nuclear complex. Positive axons of the ascending and descending CA
pathways are clearly observed. Note the TH-IR neurons of the A8
primordium just rostral to the isthmo-mesencephalic (mes) boundary.
Scale bar ⫽ 200 µm. Reproduced from Puelles L, Verney C. 1998. Early
neuromeric distribution of tyrosine-immunoreactive neurons in human embryos. J Comp Neurol 394:283–308, with permission.
34
C. VERNEY
meric migration (Fig.5 A–C). Within r1 segment, the
anlage of the locus coeruleus (A6) and its cerebellar
extension (A4) are labeled by both TH- and DBHantisera (Fig. 5 D, E).
The hindbrain of older embryos corresponding to 5 to
6 postovulatory weeks (Carnegie stage from 16 to18)
exhibits a larger number of TH positive neurons (Fig.
6). These cells are observed close to the motor nuclei,
located near the boundary between the basal and alar
plates (Nobin and Björklund, 1973; Puelles and Verney,
1998; Robert et al., 1984). TH-IR neurons of A1/C1 are
associated with the ambiguus motor nucleus, and those
of A2/C2 with the dorsal motor nucleus of vagus. These
cell groups are located in rhombomeres r7–r8. The
caudal part of A5 is near the facial motor nucleus
whereas its rostral part is contiguous to the trigeminal
motor nucleus. In the human infant hindbrain, Robert
and collaborators (1984) reported similar TH positive
neurons but identified the former part as A5 group and
the latter as A7 group. The locus coeruleus clearly
extends from the isthmus to r1/r2 boundary in our
material, whereas the subcoeruleus group appears to
be restricted to r2–r3, typically formed by larger cells
lacking DBH immunoreactivity at this stage (Puelles
and Verney, 1998).
Midbrain and Diencephalon. In the midbrain of
an embryo of 4.5 postovulatory weeks (Carnegie stage
15), the major TH-IR basal plate population coincides
topographically with the oculomotor neurons and nerve
root (Figs. 4A, 5A). Almquist et al. (1996) have recently
shown a similar labeling in a 4.5-week-old embryo and
interpreted the latter cell group as the prospective
dopaminergic A9–A10 groups. We do not share this
interpretation and believe that only the contiguous rare
TH-IR cells observed at the medial floor plate of this
same embryo represent the earliest anlage of the
A9–A10 dopaminergic populations.
During the 5–6 gestational weeks, the medial ventral
tegmentum of the midbrain displays an increase in the
number of packed TH-IR neurons corresponding to the
anlage of A8-A9-A10 groups, which are generated in the
mesencephalon but also in the contiguous prosomeres
up to the mammillary bodies (Figs. 2B, 4B, 7A).
We have studied in detail this region since it has not
been clearly described in embryological studies. The
analysis of adjacent sagittal and frontal sections stained
by Nissl technique and immunostained for TH and
DBH as well as for the differentiation markers such as
calretinin and calbindin-D28K, allowing for the characterization of the relevant transverse interneuromeric
boundary of different neuromeres and the limits between roof, alar, basal and floor plates (Puelles and
Verney, 1998; Verney et al., 1992) (Figs. 4B, 7). The
isthmic fovea and the trochlear decussation represent
the border between the isthmus and the mesencephalon, the posterior commissure marks the boundary
between the mesencephalon and the prosomere 1. The
fasciculus retroflexus marks the limit between the
prosomeres p1–p2, the zona limitans intrathalamica is
located between p2–p3, and the mammillary pouch is
present at the boundary between p3 and p4 (Verney et
al., unpublished data).
Most of the TH positive neurons of A8-A9-A10 groups
are generated during the 5–7 postovulatory weeks in
the ventricular zone of the floor plate. They migrate at
first radially and later laterally within the basal plate.
A few DA neurons are generated in the medial basal
plate close to the boundary with the floor plate (Fig.
7B). In the classical embryological studies, the extent of
the floor plate was restricted to the hindbrain, but the
recent reexamination of this region supports the idea of
a rostral extension of the floor plate up to the median
eminence (Kingsbury, 1920; Kuhlenbeck, 1973; see also
discussion in Puelles, 1995). Different data support this
idea, for example, the expression of annexin IV, which
defines a floor plate region that extends from the caudal
spinal cord all the way rostrally to the diencephalon
(Hamre et al., 1996). In addition, the induction in vitro
of the DA phenotype by the mesencephalic floor plate in
the chick is an argument in favor of the genesis of these
DA neurons in the floor plate of all vertebrates (Hynes
et al., 1995; Wang et al., 1995).
The DA A9 A10 neuronal groups are generated in the
midbrain as well as in the diencephalic segments p1,
p2. Neuropathologists had already pointed out that the
rostral, diencephalic third of the adult human substantia nigra (located rostral to the emergence of the third
cranial nerve) displays DA neurons that are more
resistant to neuronal death in Parkinson’s disease than
the ones located in the intermediate and caudal thirds
located within the mesencephalon (Ruberg et al., 1997;
see review in Van Domburg and Donkelaar, 1991).
Although this diencephalic DA neuronal population of
A9 group is more restricted than the mesencephalic
one, it could have acquired from its embryonic origin a
characteristic that makes it more akin to other diencephalic hypothalamic DA populations, all of which resist
cell death in this disease (Matzuk and Saper, 1985).
Diencephalon and Secondary Prosomeres (Telencephalon). At 4.5 postovulatory weeks, prosomeres
p3 to p6 display a series of TH-IR neuronal groups
mostly located in the basal plate that correspond to the
anlage of the A11–15 hypothalamic groups (Figs. 2B,
4A, 5A) (for details see in Puelles and Verney, 1998).
Although the DA hypothalamic neurons are composed
of heterogenous cell populations, the precocity detected
in humans is not observed in rodents (Ugrumov, 1994).
In humans, one or two weeks later, substantial TH-IR
Fig. 7. The area of the anlage of the substantia nigra and ventral
tegmental area at 6 postovulatory weeks (stage 18). A: On a midsagittal section, TH-IR neurons of the ventral tegmental area (vta) are
packed in the mesencephalon (mes) and decrease in number in the
prosomeres p1 and p2 (this section is schematized in Fig. 4B). Rostral
is to the left, dorsal is side up. There is a sharp caudal limit at the
isthmo-mesencephalic boundary. Note the numerous positive neurons
in the retromammillary (rm) and mammillary areas (mam). Reproduced from Puelles L, Verney C. 1998. Early neuromeric distribution
of tyrosine-immunoreactive neurons in human embryos. J Comp
Neurol 394:283–308, with permission. B,C: Serial coronal sections at
the level of the boundary between the prosomeric p1and p2 segments.
Numerous neurons are immunostained for TH (B) and calbindin D28K
(CABP) (C). The limit between these segments is the fasciculus
retroflexus (fr) indicated by an arrow in B. The black lines indicate the
limits between the floor (fp), basal (bp), and alar plates (ap). In B, the
TH positive neurons of the substantia nigra (sn) generated in the
ventricular zone (vz) of the fp and contiguous bp, migrate first
superficially and then laterally within the superficial bp. In C, a
restricted calbindin D28K positive neuronal population, is generated
in the medial fp and follow the same pattern of migration as the
TH-immunoreactive neurons. Note the calbindin D28K positive fibers
of the posterior commissure (pc). IIIv: third ventricle. Scale bars ⫽
50 µm.
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Fig. 7.
35
Fig. 8. TH and DBH-immunostaining of frontal sections at the
13th gestational week. A, B: Sequential sections of the noradrenergic
locus coeruleus (A6) labeled with TH- (A) and DBH-immunocytochemistry (B). The dorsal cell group is the locus coeruleus. Numerous
positive terminals obscure the neurons of the ventral group, the locus
subcoeruleus. C: Substantia nigra (SN): cluster of packed TH-IR
neurons (arrow) of the pars compacta (c), which send their dendrites in
the sizewise restricted pars reticulata (r). CPe, cerebral peduncle.
Scale bars ⫽ 50 µm in A, B, 100 µm in C). Reproduced from Zecevic N,
Verney C. 1995. Development of the catecholamine neurons in human
embryos and fetuses, with special emphasis on the innervation of the
cerebral cortex. J Comp Neurol 351:509–535, with permission.
Fig. 9. Frontal sections at the 7th postovulatory week. A: TH
positive cells are observed at two locations, in the ganglion terminale
(long arrow) and in the retina (thick arrow). B: Higher magnification
of the TH-IR neurons migrating along the medial part of the ganglion
terminale (gt) and nervus terminalis towards the telencephalon (tel).
op, olfactory placode; ns, nasal septum. Reproduced from Verney C, El
Amraoui A, Zecevic N. 1996. Comigration of tyrosine hydroxylase- and
gonadotropin-releasing hormone-immunoreactive neurons in the nasal area of human embryos. Dev Brain Res 97:251–259, with permission. C: Migrating retinoblasts exhibit TH-immunoreactivity in the
peripheral retina. L, crystallin lens. D: TH-positive post-migratory
round somata and fibers in the nerve fiber layer are observed in the
posterior retina. E: An enlarged view of the TH-IR retinoblasts in the
peripheral retina: the nuclei observed at different levels of the single
neuroblastic layer exhibit attachment processes to both limiting
membranes of the neural retina (arrows). In the more central retina,
postmigratory cells which have lost their attachment processes are
seen (arrowhead). Reproduced from Versaux-Botteri C, Verney C,
Zecevic N, Nguyen-Legros J. 1992. Early appearance of tyrosine
hydroxylase immunoreactivity in the retina of human embryos. Dev
Brain Res 69:283–287, with permission. Scale bars ⫽ 50 µm (B–D), 10
mm (E).
38
C. VERNEY
neuronal populations are observed in the basal plate,
around the mammillary bodies, that we have included
in A10 group, and in the arcuate region of p4, p5
segments as the anlage of A12 group. The alar TH-IR
neuronal population located along the cerebral aqueduct in the prosomeres p1–p2 corresponds to the caudal
extention of A11 group. Rostrally, the alar TH positive
cells in the zona incerta correspond to A13 group. A
band of TH positive cells are observed in the alar plate
of p4, p5, p6; overlapping the periventricular nucleus is
presumably the A14 group. TH-IR neurons migrate
toward the supraoptic nucleus (A15) whereas a separate TH-IR population is present in the anterior preoptic area across p5–p6 segments (Fig. 2B, 4B) (Su et al.,
1987; Tillet, 1994; Ugrumov, 1994).
Differentiation Features of the
Catecholaminergic Cell Bodies
As already emphasized, TH-immunoreactivity is detectable very early in different CA groups. DBH phenotype is observed as early as TH positivity in the
noradrenergic neurons of the locus coeruleus area but
in the other hindbrain CA neurons it is detected only
during the fetal period. PNMT phenotype could be
detected in the hindbrain of human specimens we had,
only from the 13th gestational week onward.
From 8 gestational weeks on, no TH positivity is
detected near the proliferative ventricular zone. This
indicates that all CA neurons are generated during the
embryonic period similarly to what has been described
for the monoaminergic cells in the Rhesus monkey
(Levitt and Rakic, 1982).
Hindbrain. At 4 months old, the noradrenergic and
adrenergic neurons of the fetal hindbrain have developed dendrites, and small fluorescent neurons are seen
in the area postrema (Nobin and Björklund, 1973). At
this age, we observed the locus coeruleus located dorsal
to the locus subcoeruleus along a rostrocaudal extention of 500 µm. TH-IR and DBH-IR neurons of the locus
coeruleus exhibited two or three long dendritic processes whereas in the the locus subcoeruleus area, a
dense network of positive terminals overlaps the positive cells (Fig. 8A,B).
Midbrain and Diencephalon. During the early
fetal period, the lateral and dorsal TH-IR neurons of
the substantia nigra and of the ventral tegmental area
differentiate earlier than the ventral and medial ones.
At 4 months old, TH-IR neurons of the A8-A9-A10
complex display the same overall distribution pattern
as in adult humans (Gaspar et al., 1983; Halliday and
Tork, 1986; Kitahama et al., 1994; Pearson et al., 1983,
1990; Van Domburg and Donkelaar, 1991; Zecevic and
Verney, 1995) but their differentiation is not yet complete. Along the rostrocaudal extention of the A9–A10
groups, the DA neurons of the dorsal horizontal band
show more differentiated features than the one located
ventrally and medially. The ventral DA neurons of the
pars compacta are clustered and develop dendrites
ventrally towards the pars reticulata which is rather
small at this stage (Figs. 2, 8C) (Zecevic and Verney,
1995). In the ventral tegmental area, TH positive
neurons display a similar distribution to that described
in adult human brain (Fig. 3) (Gaspar et al., 1983;
Pearson et al., 1983, 1990; Zecevic and Verney, 1995).
Caudal to the red nucleus and to the bulk of the
substantia nigra, TH-IR neurons of the A8 group are
dispersed within the reticular formation.
Early Expression of the Calbindin D28 Kphenotype Within a Subpopulation of Dopaminergic
Neurons of A8-A9-A10 Groups. The calbindin D28K
phenotype is observed within DA neurons of the A8-A9A10 groups as early as 5 gestational weeks in human
(Fig. 7B). Contrary to what is usually observed in many
other brain regions during development, calbindin
D28K-immunoreactivity is not transient within these
TH-IR neurons as demonstrated by double immunocytochemical labeling at different stages (Verney et al.,
1992, Verney et al., unpublished data). At the 13th
gestational week, the pattern of distribution of the DA
neuronal population expressing calbindin D28K phenotype is similar to that described in the adult: these cells
are located in a dorsal band extending from the lateral
substantia nigra to the medial ventral tegmental area
and are disseminated within the A10-A8 groups. The
presence of calbindin D28K has been hypothesized to
play a neuroprotective role in the selective neuronal
vunerability of DA neurons in Parkinson’s disease
(German et al., 1992; Hirsch et al., 1992; Lavoie and
Parent, 1991; Yamada et al., 1990). The function of this
early calbindin D28K expression is not known but, by
analogy, it could also protect these neurons from developmental cell death occurring in the substantia nigra
(Oo and Burke, 1997).
Transient Embryonic Expression of Tyrosine
Hydroxylase Immunoreactivity in Discrete
Neuronal Populations in Humans
As already mentioned for the oculomotor neurons
and root, additional TH positive cells are noticed during
early development in several areas where no CA neurons are detected in the adult. Transient expression of
cellular TH- and DBH-immunoreactivity has been detected in different discrete regions of the embryos such
as the spinal cord, the alar plate of the rhombomeres
r4–6 (Puelles and Verney, 1998; Zecevic and Verney,
1995). A transient TH positive cell population is present in the colliculi of human embryos similarly to
observations made in the colliculi of the postnatal rat
(Jaeger and Joh, 1983).
Fig. 10. Lateral sagittal sections at the 7th postovulatory week. A:
Low magnification photomicrograph of the ascending CA pathways
originating in the locus coeruleus (lc) and in the substantia nigra (sn).
TH positive axons run rostrally within the medial forebrain bundle
(mfb) to reach the ganglionic eminence (ge). B,C: TH-IR fibers
penetrate ventrally the ganglionic eminence (ge) and the lateral
telencephalic anlage. The cortical plate (cp) composed of a few rows of
neurons is indicated by short arrows. In darkfield illumination of
the same section, TH-IR axons are seen to enter the lateral anlage of
the cerebral cortex by the intermediate zone (long white arrow) below
the cp. Note the rare TH positive axons in the marginal zone above the
cortical plate. D: Dark field illumination of a sagittal dorsal section at
the 11th gestational week: in the cerebral cortex. TH-IR fibers are
located in the intermediate zone (iz), subplate layer (sp) and sparsely
in the marginal zone (mz). No positive fibers are observed in the
cortical plate (cp) or ventricular zone. cb, cerebellum; ci, inferior
colliculus; lv, lateral ventricle; sol, nucleus of the solitary tract; tel,
telencephalon. Scale bars ⫽ 250 µm in A, 100 µm in B,C, 50 µm in D.
B,C,D reproduced from Zecevic N, Verney C. 1995. Development of the
catecholamine neurons in human embryos and fetuses, with special
emphasis on the innervation of the cerebral cortex. J Comp Neurol
351:509–535, with permission.
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Fig. 10.
39
40
C. VERNEY
Two main regions of TH-immunoreactivity are noticed in humans (Fig. 9). One is the anlage of the eye
where TH-immunoreactive retinoblasts and ganglionlike cells are observed sending labeled axons into the
optic nerve of embryos of 6–7 postovulatory weeks (Fig.
9C–E). Since in the adult retina, the only TH positive
cells are a subpopulation of amacrine cells, the expression of this enzyme in some ganglion-like cells
represents either a transient developmental event or
indicates that these cells subsequently undergo transformation through axonal degeneration (Frederick et
al., 1982; Nguyen-Legros et al., 1992; Versaux-Botteri
et al., 1992). The second area is the nasal region where
TH-IR cells generated in the olfactory placode migrate
towards the medial and rostral telencephalon (Fig.
9A,B). In fact, they follow the same migratory stream as
the gonadotropin-releasing-hormone (GnRH)-containing hypothalamic neurons that are generated in the
olfactory placode and migrate towards the preoptic area
(Schwanzel-Fukuda et al., 1996). Some neurons exhibit
only the TH or GnRH phenotype and others express
both phenotypes. These neurons migrate towards the
basal forebrain and we do not know if they could
correspond to the TH-IR neuronal populations observed
in the human basal telencephalon of the adult described in a former paragraph (Verney et al., 1996).
Development of the Catecholaminergic Axons
in the Human Telencephalon
The TH positive axons are observed as soon as the
neurons are generated and migrate superficially at 4.5
postovulatory weeks (Puelles and Verney, 1998). At the
end of the embryonic period, the different pathways
described in rodents are well recognizable in humans
(Lindvall and Björklund, 1974; Nobin and Björklund,
1973; Puelles and Verney, 1998; Zecevic and Verney,
1995). Ascending and descending axons run through
the central tegmental tract (Fig. 6) from the medulla
oblongata to the mesencephalon. The noradrenergic
fibers, arising from locus coeruleus neurons, run rostrally in the dorsal tegmental bundle. They join the
ascending mesotelencephalic tract emerging from the
DA cell groups A8–A10 and form the medial forebrain
bundle (Fig. 10A). This TH-positive bundle provides
efferent fibers to the hypothalamic areas and to the
basal ganglia. Positive axons are observed in the ganglionic eminence at the end of the embryonic period (Fig.
10B). TH positive patches are noticed in the anlage of
the basal ganglia, at 13 gestational weeks (Verney,
personal observation). At this stage, and later during
prenatal period, the nigrostriatal system also expresses
several markers of DA transmission such as D1 and D2
receptors and dopamine transporter (Aubert et al.,
1997; Brana et al., 1997).
Penetration of the Noradrenergic and Dopaminergic Axons to the Anlage of the Cerebral Cortex.
No positive fibers penetrate the anlage of the cerebral
cortex at 6 gestational week in the primordial plexiform
layer, before the formation of the cortical plate. When
the first cortical plate neurons migrate at 7–8 gestational weeks in humans, the first TH positive fibers
penetrate the lateral frontal cortex. This takes place
below the cortical plate in the intermediate zone with
rare positive axons running in the marginal zone (Fig.
10B,C) (Marin-Padilla, 1970; Sidman and Rakic, 1973;
Zecevic, 1993). So, the arrival of CA axons coincides
with the formation of the cortical plate, and no THimmunoreactive axons are detected in cortical regions
where the cortical plate is absent. Such an invasion of
CA axons after the formation of the cortical plate has
also been observed in rodents by us and others
(Schlumpf et al., 1980; Verney et al., 1982, 1984). In
humans, sparse DBH-IR noradrenergic axons penetrate the telencephalic wall in a pattern similar to that
described for TH-IR fibers and following the same
timing. During the following three to four weeks, the
invasion of CA fibers does not follow the lateral to
medial gradient of formation of the cortical plate
(Zecevic, 1993), because the fronto-medial cortical areas are penetrated before the dorsal cortex. The ‘‘waiting period,’’ when the TH-IR axons are restricted to the
subplate layer and intermediate zone without penetrating the cortical plate, lasts for approximately 4 weeks.
The subplate layer, that is particularly thick in humans, is known to represent a transitional layer containing differentiated neurons, afferent fibers (first thalamic fibers) and the first synapses (Kostovic and Rakic,
1980, 1990; Shatz et al., 1988). In our results, the CA
fibers arrive in this ‘‘waiting compartment’’ from the 8
postovulatory weeks on, before the other afferents
currently identified in humans. The callosal and corticocortical connections start to develop at 12–13 gestational weeks (Rakic and Yakovlev, 1968) in parallel with
the subcortical (mostly thalamic) afferences currently
visualized by their acetylcholinesterase positivity
(Candy et al., 1985; Kostovic and Goldman-Rakic,
1983). In fact, in rodents, the first thalamic afferents
are known to penetrate the subplate layer of cortical
anlage in similar timing as the CA axons (Molnar and
Blackmore, 1995; Verney et al., 1982, 1984). Therefore,
one could expect the first human thalamic afferents to
penetrate the cortical anlage as early as 8 gestational
weeks. The first synapses in the developing human
cortex are observed above and below the cortical plate
at 7 gestational weeks (Molliver et al., 1973; Larroche
and Houcine, 1982). Involvement of the CA fibers in the
earliest, transient synapses in the subplate layer has
not been directly demonstrated, but in the monkey
cortex the earliest synapses often contain dense core
vesicles, suggesting that they can be CA (Zecevic et al.,
1989). A rostrocaudal gradient of penetration of CA
fibers is observed with a clear invasion of the subplate
layer of the occipital pole at the 13th gestational week.
At that time, the TH-IR axons penetrate the cortical
plate in the rostral areas, mostly ascending from fibers
in the subplate layer, rarely descending from the marginal zone.
Further Development of the Noradrenergic and
Dopaminergic Fibers and Terminals in the Cerebral Cortex. In 20–24-week-old human fetuses, a
widespread TH-IR and DBH-IR innervation is observed
in a regional and laminar specific pattern of distribution in the frontal cortex (Fig.11) (Verney et al., 1993).
The densest dopaminergic TH positive innervation is
observed in the anlage of the motor, cingulate and
insular cortices whereas a lower density is detected in
the rostral prefrontal cortical anlage. DBH-IR noradrenergic afferents are less numerous than dopaminergic
Fig. 11. Fetus of 24 gestational weeks. Contiguous 10-mm-thick
cryostat sections of the dorsofrontal cortex in the presumable motor
area. A: Dark-field illumination of TH-IR fibers distributed in the
whole thickness of the cortex . B: Nissl stained section. The neurons of
the cortical plate (cp) are not densely packed (except in layer II) as
they started to fifferentiate, but the cortical layering is yet not visible.
C: dark field illumination of DBH-IR fibers at the same level. Scale
bar ⫽ 100 µm. Reproduced from Verney C, Milosevic A, Alvarez C,
Berger B. 1993. Immunocytochemical evidence of well-developed
dopaminergic and noradrenergic innervations in the frontal cerebral
cortex of human fetuses at midgestation. J Comp Neurol 336:331–344,
with permission of the publisher.
42
C. VERNEY
Fig. 12. TH-labeled axons in the frontal medial area 9 at different
postnatal stages in Rhesus monkey observed on 40-µm-thick cryostat
sections. To compare the density of TH-positive axons of these
postnatal stages to that observed at a prenatal stage shown in Figure
11, the different thickness of the sections made in both cases must be
taken into account. A–C: Darkfield photomicrographs of TH immunoreactivity. The density of labeled axons is increasing especially in layer
III to reach its maximal value in the adolescent animals (2.75-yearold) before declining to adult levels (5.7-year-old). Scale bars ⫽ 200
µm. D,G: Examples of recontructions, using the Eutectic Neuron
Tracing System, of TH-labeled axons and varicosities in deep layer III
from animals of the following ages: 8 days (D), 37 days (E), 2.8 years
(F), and 5.7 years (G). Reproduced from Rosenberg DR, Lewis DA.
1995. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol 358:383–400, with permission of
the publisher.
TH positive ones in all the cortical areas studied (Fig.
11). In all areas, the upper subplate and the lower part
of the cortical plate exhibit a dense TH and DBH-IR
axonal innervation whereas fewer axons are present in
the molecular layer and intermediate zone. Surprisingly, the pattern of distribution and even the density of
fibers are already comparable to those described previously in the adult human cerebral cortex using similar
techniques (Gaspar et al., 1989; Verney et al., 1993). At
the time when the CA afferents invade the different
areas and layers of the frontal cortex, all cortical
neurons have been generated but their migration has
not ended and the differenciation process is far from
completion (Rakic, 1988). It is difficult to compare the
pattern of distribution of CA axons at midgestation
with that found in the adult since the cortical layering
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
is not visible at midgestation. The more obvious difference between these two stages is the low density of DA
axons in layer I of the fetal frontal cortex while this
layer is one of the most densely innervated layer at
birth (Lewis and Harris, 1991) and in adult primates
(Fig. 12) (Berger et al., 1988; Gaspar et al., 1989; Lewis
et al., 1987). In the adult monkey cerebral cortex, the
majority of the DA synapses are located on spines of
pyramidal cells dendrites (Smiley and Goldman-Rakic,
1993; Smiley et al., 1992), which are not yet present
early in gestation. The bulk of synaptogenesis in monkeys occurs during the second half of gestation and
during the first postnatal weeks (Bourgeois et al., 1994;
Zecevic et al., 1989), in parrallel with the appearance of
binding sites for DA receptors (Lidow et al., 1991).
During the protracted prenatal and postnatal periods, a
reorganization in the distribution of DA fibers and
terminals is likely to occur in humans as it has been
described for monkeys (Foote and Morrison, 1984;
Rosenberg and Lewis, 1995). Rosenberg and Lewis
(1995) have observed a transient sprouting of DA fibers
and terminal fields in layer III of the prefrontal monkey
cortex during postnatal development with a peak at
adolescence and a decrease in adulthood (Fig. 12). One
might expect a similar discontinuity in the growth of
CA terminal field in the developing human cerebral
cortex.
Conclusions
Our results on early development reveal important
information for the use of the first trimester mesencephalic tissue as donor material in clinical trials for
treatment of Parkinson’s disease (Lindvall et al., 1992).
First, the sampling of the anlage of the substantia nigra
should be made at the mesencephalic level as well as
anteriorly in the prosomeres p1–p2 and, second, this
sampling should be done early in development, around
6–7 gestational weeks, when all the DA neurons are
being generated but before the development of the
extended ascending axonal pathways.
In primates, the development of CA neurons occurs
earlier than in rodents when normalized to the length
of gestation. In fact, the overall pattern of early development of the CA systems appears to be phylogenetically
well preserved in mammals. This is particularly true
for the development of the noradrenergic and adrenergic cell bodies located in the rhombencephalon, and for
the DA neurons of the midbrain. However, the DA
neuronal populations distributed in the diencephalon
and telencephalon cell groups display specific features
unique to humans when compared to rodents: (1) in
humans, numerous DA neurons are detected in mammillary areas early in development whereas only rare
neurons are detected in rodents, (2) the hypothalamic
DA cell groups are particularly precocious in humans
and there is an important DA neuronal subpopulation
in the supraoptic nucleus which is specific to humans,
(3) numerous TH-IR, presumably DA neurons, are
detected in the human basal telencephalon, and (4)
there is a widespread DA innervation in all the different
areas and layers of the human cerebral cortex as
compared to the innervation in restricted cortical areas
in rodents. The precocity of development of the DA
innervation in early fetal life raises once again the
43
difficult question on their role during the protracted
prenatal and early postnatal period in man. Recently,
the presence of a monoamine, serotonin, within the
developing thalamic efferents towards the cerebral
cortex in mice has been shown to be essential for the
cytoarchitectonic differentiation of the barrel fields in
the somatosensory cortex. Moreover, monoaminergic
transporters have also been found in the thalamocortical system (Cases et al., 1996; Lebrand et al., 1996,
1998). It would be interesting to see if similar expression of monoamine transporters is present during the
early thalamic development in humans.
ACKNOWLEDGMENTS
The author is indebted to Prof. L. Puelles for his great
help brought in the understanding of the organization
of the human embryos and Dr. N. Zecevic for providing
the embryonic specimens. We thank A.Vigny and J.P.
Henry, who gave us the anti-TH and anti-DBH antibodies, respectively, Drs. P. Gaspar, E. Bloch-Gallego, P.
Gressens, and K. Kultas-Ilinsky for critical reading of
the manuscript, and Chantal Alvarez and Aude Muzerelle for technical work.
REFERENCES
Almqvist PM, Akesson E, Wahlberg LU, Pschera H, Seiger A, Sundstrom E. 1996. First trimester of the human nigrostriatal dopamine
system. Exp Neurol 139:227–237.
Alterio J, Ravassard P, Haavik J, Le Caer JP, Faucon Binet N,
Waksman G, Mallet J. 1998. Human tyrosine hydroxylase isoforms.
Inhibition by excess tetrahydropterin and unusual behavior of
isoforms 3 after cAMP-dependent protein kinase phosphorylation. J
Biol Chem 273:10196–10201.
Altman J, Bayer SA. 1981. Development of the brain stem in the rat. V.
Thymidine-radiographic study of the time of origin of neurons in the
midbrain tegmentum. J Comp Neurol 198:677–716.
Arango V, Ruggiero DA, Callaway JL, Anwar M, Mann JJ, Reis DJ.
1988. Catecholamine neurons in the ventrolateral medulla and
nucleus of the solitary tract in the human. J Comp Neurol 273:224–
240.
Aubert I, Brana C, Pellevoisin C, Giros B, Caille I, Carles D, Vital C,
Bloch B. 1997. Molecular anatomy of the development of the human
substantia nigra. J Comp Neurol 379:72–87.
Bear MF, Singer W. 1986. Modulation of cortical plasticity by acetylcholine and noradrenaline. Nature 320:172–176.
Berger B, Gaspar P. 1994. Comparative anatomy of the catecholaminergic innervation of rat and primate cerebral cortex. In: Smeets
WJAJ, Reiner A, editors. Phylogeny and development of catecholamine systems in the CNS of vertebrates. Cambridge: University
Press. p 293–324.
Berger B, Verney C. 1984. Development of the catecholamine innervation in rat neocortex; morphological features. In: Descarries L,
editor. Monoamine innervation of cerebral cortex. New York: Alan R.
Liss Inc. p 95–121.
Berger B, Trottier S, Gaspar P, Verney C, Alvarez C. 1986. Major
dopamine innervation of the cortical motor areas in the Cynomolgus
monkey. A radioautograghic study with comparative assessment of
serotoninergic afferents. Neurosci Lett 72:121–127.
Berger B, Trottier S, Verney C, Gaspar P, Alvarez C. 1988. Regional
and laminar distribution of the dopamine and serotonin innervation
in the Macaque cerebral cortex: a radioautographic study. J Comp
Neurol 273:99–119.
Berger B, Gaspar P, Verney C. 1991. Dopaminergic innervation of the
cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci 14:21–27.
Berger B, Verney C, Goldman-Rakic PS. 1992. Prenatal monoaminergic innervation of the cerebral cortex: differences between rodents
and primates. In: Kostovic I, Knezevic S, Wisniewski H, Spilich G,
editors. Neuroanatomy, aging and cognition. Boston: Birkhäuser
Inc. p. 35–121.
Bergquist H, Källen B. 1954. Notes on the early histogenesis and
morphogenesis of the central nervous system in vertebrates. J Comp
Neurol 100:627–660.
44
C. VERNEY
Betardet R, Turner,R, Chockkan,V, DeLong MR, Allers KA, Walters J,
Levey AI, Greenamyre JT. 1997. Dopaminergic neurons intrinsic to
the primate striatum. J Neurosci 17:6761–6768.
Björklund A, Lindvall O. 1984. Dopamine-containing systems in the
CNS. In: Björklund A, Hökfelt T, editors. Handbook of chemical
neuroanatomy. Vol 2: classical transmitters in the CNS. Part 1.
Amsterdam: Elsevier. p 55–122.
Blakely R, De Felice LJ, Hartzell HC. 1994. Molecular physiology of
norepinephrine and serotonin transporters. J Exp Biol 196:263–281.
Blue ME, Parnavelas JG. 1982. The effect of neonatal 6-hydroxydopamine treatment on synaptogenesis in the rat visual system. J Comp
Neurol 205:199–205.
Bogerts B. 1981. A brain atlas of catecholaminergic neurons in man,
using melanin as a natural marker. J Comp Neurol 197:63–80.
Bourgeois JP, Goldman-Rakic PS, Rakic P. 1994. Synaptogenesis in
the prefrontal cortex of rhesus monkeys. Cereb Cortex 4:78–96.
Brana C, Aubert I, Charron G, Pellevoisin C, Bloch B. 1997. Ontogeny
of the striatal neurons expressing the D2 dopamine receptor in
humans: an in situ hybridization and receptor-binding study. Mol
Brain Res 48:389–400.
Bulfone AP, Puelles L, Porteus MH, Frohman MA, Martin GR,
Rubenstein JLR. 1993. Spacially restricted expression of Dlx–1
Dlx–2 (Tes–1) Gbx–2, and Wnt–3 in the embryonic day 12.5 mouse
forebrain defines potential transverse and longitudinal segmental
boundaries. J Neurosci 13:3155–3172.
Candy JM, Perry EK, Perry RH, Bloxam CA, Thompson J, Johnson M,
Oakley AE, Edwardson JA. 1985. Evidence for the early prenatal
development of cortical cholinergic afferents from the nucleus of
Meynert in the human foetus. Neurosci Lett 61:91–95.
Cases O, Vitalis T, Seif I, De Mayer E, Sotelo C, Gaspar P. 1996. Lack of
barrels in the somatosensory cortex of monoamine oxydase Adeficient mice: role of a serotonin excess during the critical period.
Neuron 16:297–307.
Choi BH, Antanitus DS, Lapham LW. 1975. Fluorescence histochemical and ultractructural studies of locus coeruleus of human fetal
brain. Neuropathol Exp Neurol 6:507–516.
Dahlström A, Fuxe K. 1964. Evidence for the existence of monoaminecontaining neurons in the central nervous system. I. Demonstration
of monoamines in the cell bodies of the brain stem neurons. Acta
Neuropathol Suppl 62 (Suppl 232):1–55.
Deutch AY. 1993. Prefrontal cortical dopamine systems and the
elaboration of functional corticostriatal circuits: implications for
schizophrenia and Parkinson’s disease. J Neural Transm 91:197–
221.
Dubach M. 1994. Telencephalic dopamine cells in monkeys, human,
and rats. In. Smeets WJAJ, Reiner A, editors. Phylogeny and
development of catecholamine systems in the CNS of vertebrates.
Cambridge: Cambridge University Press. p 273–292.
Dumas S, Le Hir H, Bodeau-Péan S, Hirsch E, Thermes C, Mallet J.
1996. New species of human tyrosine hydroxylase mRNA are
produced in variable amounts in adrenal medulla and are overexpressed in progressive supranuclear palsy? J Neurochem 67:19–25.
Falck B, Hillarp NA, Thieme G, Torp A. 1962. Fluorescence of
catecholamines and related compounds with formaldehyde. J Histochem Cytochem 10:348–354.
Foote SL, Morrison JH. 1984. Postnatal development of laminar
innervation patterns by monoaminergic fibers in monkey (Macaca
Fascicularis) primary visual cortex. J Neurosci 11:2667–2680.
Foster GA. 1994. Ontogeny of catecholaminergic neurons in the
central nervous system of mammalian species: general aspects. In:
Smeets WJAJ, Reiner A, editors. Phylogeny and development of
catecholamine systems in the CNS of vertebrates. Cambridge:
Cambridge University Press. p 405–430.
Frederick JM, Rayborn ME, Laties AM, Lam DMK, Hollyfield JG.
1982. Dopaminergic neurons in the human retina. J Comp Neurol
65–70.
Freeman TB, Spence MS, Boss BD, Spector DH, Strecker RE, Olanow
CW, Kordower JH. 1991. Development of dopaminergic neurons in
the human substantia nigra. Exp Neurol 113:344–353.
Gaspar P, Berger B, Gay M, Hamon M, Cesselin F, Vigny A, Javoy-Agid
F, Agid Y. 1983. Tyrosine hydroxylase and methionine-enkephalin in
the human mesencephalon. J Neurol Sci 58:247–267.
Gaspar P, Berger B, Alvarez C, Vigny A, Henry JP. 1985. Catecholamine innervation of the septal area in man: Immunocytochemical
study using TH and DBH antibodies. J Comp Neurol 241:12–33.
Gaspar P, Berger B, Febvret A, Krieger-Poulet M, Borri-Voltatorni C.
1987. Tyrosine-hydroxylase-immunoreactive neurons in the human
cerebral cortex: a novel catecholaminergic group? Neurosci Lett
80:257–262.
Gaspar P, Berger B, Febvret A, Vigny A, Henry JP. 1989. Catecholamine innervation of the human cerebral cortex as revealed by
comparative immunohistochemistry of tyrosine hydroxylase and
dopamine-Beta-hydroxylase. J Comp Neurol 279:249–271.
Gaspar P, Stepniewska I, Kaas JH. 1992. Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal
cortex in owl monkeys. J Comp Neurol 325:1–21.
Gaspar P, Heizmann CW, Kaas JH. 1993. Calbindin D–28K in the
dopaminergic mesocortical projection of a monkey (Aotus trivirgatus). Brain Res 603:166–172.
Giros B, El Mestikawy S, Godinot N, Zhneg N, Han H, Yang-Feng T,
Caron MG. 1992. Cloning, pharmacological characterization, and
chromosome assignment of the human dopamine transporter. Mol
Pharmacol 42:383–390.
Geffard M, Buijs RM, Séguéla P, Pool CW, Le Moal M. 1984. First
demonstration of highly specific and sensitive antibodies against
dopamine. Brain Res 82:161–165.
Gerfen CR. 1992. The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci 13:133–139.
German DC, Schlusselberg DS, Woodward DJ. 1983. Tree-dimensional Computer reconstruction of midbrain dopaminergic neuronal
populations: from mouse to man. J Neural Transm 57:243–254.
German DC, Manaye KF, Sonsalla PK, Brooks BA. 1992. Midbrain
dopaminergic cell loss in Parkinson’s disease and MPTP-induced
Parkinsonism: sparing of calbindin-D28k-containing cells. Ann NY
Acad Sci 648:42–62.
Gouras GK, Rance NE, Scott Young III W, Koliatsos VE. 1992.
Tyrosine-hydroxylase-containing neurons in the primate basal forebrain magnocellular complex. Brain Res 584:287–293.
Grace AA. 1993. Cortical regulation of subcortical dopamine systems
and its possible relevance to schizophrenia. J Neural Transm
91:111–134.
Graybiel AM. 1990. Neurotransmitters and neuromodulators in the
basal ganglia. Trends Neurosci 13:244–253.
Grima B, Lamouroux A, Boni C, Julien JF, Javoy-Agid F, Mallet J.
1987. A single human gene encoding multiple tyrosine-hydroxylase
with different predicted functional characteristics. Nature 326:707–
711.
Haber SN, Groenewegen HJ. 1990. Inter relationship of the distribution of neuropeptides and tyrosine hydroxylase immunoreactivity in
the human substantia nigra. J Comp Neurol 290:53–68.
Halasz N, Shepherd GM. 1983. Neurochemistry of the vertebrate
olfactory bulb. Neuroscience 10:579–621.
Halliday GM, Törk I. 1986. Comparative anatomy of the ventromedial
mesencephalic tegmentum in the rat, cat, monkey and human. J
Comp Neurol 423:445.
Halliday GM, Li YW, Joh TH, Cotton RG.H, Howe PRC, Geffen LB,
Blessing WW. 1988. Distribution of monoamine-synthesizing neurons in the human medulla oblongata. J Comp Neurol 273:301–317.
Hamre KM, Keller-Peck CR, Campbell RM, Peterson AC, Mullen RJ,
Goldowitz D. 1996. Annexin IV is a marker of roof and floor plate
development in the murine CNS. J Comp Neurol 368:527–537.
Hirsch EC, Mouatt A, Thomasset M, Javoy-Agid F, Agid Y, Graybiel
AM. 1992. Expression of CalbindinD28k-like immunoreactivity in
catecholaminergic cell groups of the human midbrain: normal
distribution and distribution in Parkinson’s disease. Neurodegeneretion 1:83–93.
Hornung JP, Tork I, De Tribolet N. 1989. Morphology of tyrosine
hydroxylase-immunoreactive neurons in the human cerebral cortex.
Exp Brain Res 76:12–20.
Hökfelt T, Fuxe K, Goldstein M, Johansson O. 1974. Immunohistochemical evidence for the existence of adrenaline neurons in the rat
brain. Brain Res 66:235–251.
Hökfelt T, Martensson R, Björklund A, Goldstein M. 1984. Distributional maps of tyrosine hydroxylase-immunoreactive neurons in the
rat brain. In: Björklund A, Hökfelt T, editors. Handbook of chemical
neuroanatomy, Vol 2: classical transmitters in the CNS, Part 1.
Amsterdam: Elsevier Science. p 277–379.
Hynes M, Poulsen K, Tessier-Lavigne M, Rosenthal A. 1995. Control of
neuronal diversity by the floor plate: Contact-mediated induction of
midbrain dopaminergic neurons. Cell 80:95–101.
Ikemoto K, Kitahama K, Jouvet A, Arai R, Nishimura A, Nishi K,
Nagatsu I. 1997. Demonstration of L-dopa decarboxylating neurons
specific to human striatum. Neurosci Lett 232:111–114.
Jaeger CB, Joh TH. 1983. Transient expression of tyrosine hydroxylase in some neurons of the developing inferior colliculus of the rat.
Dev Brain Res 11:128–132.
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Kasamatsu T, Pettigrew JD. 1976. Depletion of brain catecholamines:
Failure of ocular dominance shift after monocular occlusion in
kittens. Science 194:206–209.
Kasamatsu T, Pettigrew JD, Ary M. 1981. Cortical recovery from
effects of monocular deprivation: Acceleration with norepinephrine
and suppression with 6-hydroxydopamine. J Neurophysiol 45:254–
266.
Kaneda N, Kobayasho K, Ichinose H Kishi H, Kanazawa A, Kurosawa,Y, Fujita K, Nagatsu T. 1987. Isolation of a novel cDNA clone for
human tyrosine hydroxylase: alternative RNZ splicing procedures
four kinds of mRNA from single gene. Biophys Res Commun
146:971–975.
Kemper CM, O’Conner DT, Westlund KN. 1987. Immunocytochemical
localization of dopamine-B-hydroxylase in neurons of the human
brain stem. Neuroscience 981–989.
Kingsbury BF. 1920. The extend of the floor plate of His and its
significance. J Comp Neurol 32:113–135.
Kitahama K, Pearson J, Denoroy L, Kopp N, Ulrich J, Maeda T, Jouvet
M. 1985. Adrenergic neurons in human brain demonstrated by
immunohistochemistry with antibodies to phenylethanolamine-Nmethyltransferase(PNMT): discovery of a new group on the nucleus
of the tractus solitarius. Neurosci Lett 53:303–308.
Kitahama K, Denoroy L, Goldstein M, Jouvet M, Pearson J. 1988.
Immunohistochemistry of tyrosine hydroxylase and phenylethalolamine N-methyltransferase in the human brain stem: description
of adrenergic perikarya and characterization of longitudinal catecholaminergic pathways. Neuroscience 25:97–111.
Kitahama K, Nagatsu I, Pearson J. 1994. Catecholamine systems in
mammalian midbrain and hindbrain: theme and variation. In:
Smeets WJAJ, Reiner A, editors. Phylogeny and development of
catecholamine systems in the CNS of vertebrates. Cambridge:
Cambridge University Press. p 183–206.
Kitahama K, Sakamoto N, Jouvet A, Nagatsu I, Pearson J. 1996.
Dopamine-B-hydroxylase and tyrosine hydroxylase immunoractive
neurons in the human brain stem. J Chem Neuroanat 10:136–146.
Kostovic I, Goldman-Rakic PS. 1983. Transient cholinesterase staining in the mediodorsal nucleus of the thalamus and its connections
in the developing human and monkey brain. J Comp Neurol
219:431–447.
Kostovic I, Rakic P. 1980. Cytology and the time of origin of interstitial
neurons in the white matter in infant and adult human and monkey
telencephalon. J Neurocytol 9:219–242.
Kostovic I, Rakic P. 1990. Developmental history of the transient
subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 297:441–470.
Köhler C, Everitt BJ, Pearson J, Goldstein M. 1983. Immunohistochemical evidence for a new group of catecholamine-containing
neurons in the basal forebrain of the monkey. Neurosci Lett
37:161–166.
Kuhlenbeck H. 1973. The central nervous system of vertebrates.
Berlin: Karger A.G.
Kuljis RO, Martmn-Vasallo P, Peress NS. 1989. Lewy bodies in
tyrosine hydroxylase synthesizing neurons of the human cerebral
cortex. Neurosci Lett 106:49–54.
Larroche JC, Houcine O. 1982. Le néo-cortex chez l’embryon et le
foetus humain. Apport du microscope électronique et du Golgi.
Reprod Nutr Dév 22:163–170.
Lauder JM, Bloom FE. 1974. Ontogeny of monoamine neurons in the
locus coeruleus, raphe nuclei and substantia nigra of the rat. I. Cell
differentiation. J Comp Neurol 155:469–481.
Lavoie B, Parent A. 1991. Dopaminergic neurons expressing calbindin
in normal and parkinsonian monkeys. Neuroreport 2:601–604.
Lebrand C, Cases O, Adelbrecht C, Doye A, Alvarez C, El Mestikawy S,
Seif I, Gaspar P. 1996. Transient uptake and storage of serotonin in
developing thalamic neurons. Neuron 17:823–835.
Lebrand C, Cases O, Wehrlé R, Blakely RD, Edwards RH, Gaspar P.
1998. Transient developmental expression of monoamine transporters in the rodent forebrain. J Comp Neurol 401:506–524.
Levitt P, Moore RY. 1978. Noradrenaline neuron innervation of the
neocortex of the rat. Brain Res 139:219–232.
Levitt P, Rakic P. 1982. The time of genesis, embryonic origin and
differentiation of the brain stem monoamine neurons in the rhesus
monkey. Dev Brain Res 4:35–57.
Lewis DA. 1997. Development of the prefrontal cortex during adolescence: Insights into vulnerable neural circuits in schizophrenia.
Neuropsychopharmacology 16:385–398.
Lewis DA, Harris HW. 1991. Differential laminar distribution of
tyrosine hydroxylase-immunoreactive axons in infant and adult
monkey prefrontal cortex. Neurosci Lett 125:151–154.
45
Lewis DA, Morrisson JH. 1989. Noradrenergic innervation of monkey
prefrontal cortex: A dopamine-B-hydroxylase immunohistochemical
study. J Comp Neurol 282:317–330.
Lewis DA, Campbell MJ, Foote SL, Goldstein M, Morrison JH. 1987.
The distribution of tyrosine-hydroxylase immunoreactive fibers in
primate neocortex is widespread but regionally specific. J Neurosci
7:279–290.
Lewis DA, Melchitzky DS, Gioio A, Salomon Z, Kaplan BB. 1991.
Neuronal localization of tyrosine hydroxylase gene products in
human neocortex. Mol Cell Neurosci 2:228–234.
Lewis DA, Melchitzy DS, Haycock JW. 1993. Four isoforms of tyrosine
hydroxylase are expressed in human brain. Neuroscience 54:477–
492.
Li YW, Halliday GM, Joh TH, Geffen LB, Blessing WW. 1988. Tyrosine
hydroxylase-containing neurons in the supraoptic and paraventricular nuclei in the adult human. Brain Res 461:75–86.
Lidow MS, Goldman-Rakic PS, Rakic P. 1991. Synchronized overproduction of neurotransmitter receptor expression in the primate
neocortex during postnatal development. Proc Natl Acad Sci USA
88:10218–10221.
Lindvall O, Björklund A. 1978. Organization of catecholamine neurons
in the rat central nervous system. In: Iverson LL, Iversen SD,
Snyder SH, editors. Handbook of psychopharmacology, Vol. 9. New
York: Plenum Publishing. p 139–231.
Lindvall O, Björklund A. 1983. Dopamine- and norepinephrinecontaining neuron systems: their anatomy in the rat brain. In:
Emson PC, editor. Chemical neuroanatomy. New York: Raven Press.
p 229–255.
Lindvall O, Widner H, Rehncrona S, Brundin P, Odin P, Gustavii B,
Frackowiak R, Leenders KL, Sawle G, Rothwell JC, Björklund A,
Marsden CD. 1992. Transplantation of fetal dopamine neurons in
Parkinson’s disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol
31:155–165.
Lumsden A, Keynes R. 1989. Segmental patterns of neuronal development in the chick hindbrain. Nature 337:424–428.
Maeda T, Ikemoto K, Satoh K, Kitahama K, Geffard M. 1995.
Dopaminergic innervation of primate cerebral cortex: an immunohistochemical study in the macaque monkey. In: Segawa M, Nomura Y,
editors. Age related monoamine dependent disorders and their
modulation by gene and gender. Basel: Karger. p 147–159.
Marin-Padilla M. 1970. Prenatal and early postnatal development of
the human motor cortex: a golgi study. I.The sequential development of the cortical layers. Brain Res 23:167–183.
Matzuk MM, Saper CB. 1985. Preservation of hypothalamic dopaminergic neurons in Parkinson’s disease. Ann Neurol 18:552–555.
McRitchie DA, Hardman CD, Halliday GM. 1996. Cytoarchitectural
distribution of calcium binding proteins in midbrain dopaminergic
regions of rats and humans. J Comp Neurol 364:121–150.
Molliver ME, Kostovic I, Van Der Loos H. 1973. The development of
synapses in cerebral cortex of the human fetus. Brain Res 50:403–
407.
Molnár Z, Blakemore C. 1995. How do thalamic axons find their way to
the cortex. Trends Neurosci 18:389–397.
Morrison JH, Grzanna R, Molliver ME, Coyle JT. 1978. The distribution and orientation of noradrenergic fibers in neocortex of the rat:
an immunofluorescence. J Comp Neurol 181:17–40.
Morrison JH, Foote SL, O’Connor D, Bloom FE. 1982. Laminar,
tangential and regional organization of the noradrenergic innervation of the monkey cortex: dopamine-b-hydroxylase immunoreactivity. Brain Res Bull 9:309–319.
Nguyen-Legros J, Durand J, Simon A. 1992. Catecholamine cell types
in the human retina. Clin Vision Sci 147:435–447.
Noack HJ, Lewis DA. 1992. Antibodies directed against tyrosine
hydroxylase differentially recognize noradrenergic axons in monkey
neocortex. Brain Res 500:313–324.
Nobin A, jörklund A.1973. Topography of the monoamine neuron
systems in the human brain as revealed in fetuses. Acta Physiol
Scand (Suppl) 88:1–40.
Oertel WH, Tappaz ML, Berod A, Mugnaini E. 1982. Two-color
immunohistochemistry for dopamine and GABA neurons in rat
substantia nigra and zona incerta. Brain Res Bull 9:463–474.
Olson L, Seiger Å. 1972. Early prenatal ontogeny of central monoamine neurons in the rat: Fluorescence histochical observations. Z
Anat Entwickl Gesch 137:301–316.
Olson L, Boreus LO, Seiger A. 1973. Histochemical demontration and
mapping of 5-hydroxytryptamine-and catecholamine-containing neuron systems in the human fetal brain. Z Anat Entwicklungsgesch
139:259–282.
46
C. VERNEY
Olszewski J, Baxter D. 1954. Cytoarchitecture of the human brain.
Basel: Karger.
Oo TF, Burke R. 1997. The time course of developmental cell death in
phenotypically defined dopaminergic neurons of the substantia
nigra. Dev Brain Res 98:191–196.
O’Rahilly R, Gardner E. 1971. The timing and sequence of events in
the developpement of the human nervous system during the embryonic period proper. Z Anat Entwickl Gesch 134:1–12.
O’Rahilly R, Muller F, Hutchins GM, Moore GW. 1987. Computer
ranking of the sequence of appearance of 73 features of the brain
and related structures in staged human embryos during the sixth
week of development. Am J Anat 180:69–86.
Panayotacopoulou MT, Swaab DF. 1993. Development of tyrosineimmunoreactive neurons in the human paraventricular and supraoptic nucleus. Dev Brain Res 145:150
Pearson J, Brandeis L, Goldstein M. 1980. Appeareance of tyrosine
hydroxylase immunoreactivity in the human embryo. Dev Neurosci
3:140–150.
Pearson J, Goldstein M, Markey K, Brandeis L. 1983. Human brainstem catecholamine neuronal anatomy as indicated by immunocytochemistry with antibodies to tyrosine hydroxylase. Neuroscience
8:3–32.
Pearson J, Halliday G, Sakamoto N, Michel JP. 1990. Catecholaminergic neurons. In: Paxinos G, editor. The human nervous system. San
Diego: Academic Press. p 1023–1049.
Pickel VM, Specht LA, Sumal KK, Joh TH, Reis DJ, Hervonen A. 1980.
Immunocytochemical localization of tyrosine hydroxylase in the
human fetal nervous system. J Comp Neurol 194:465–474.
Porrino LJ, Goldman-Rakic PS. 1982. Brainstem innervation of
prefrontal and anterior cingulate cortex in the Rhesus Monkey
revealed by retrograde transport of HRP. J Comp Neurol 205:63–76.
Puelles L. 1995. A segmental morphological paradigm for understanding vertebrate forebrains. Brain Behav Evol 46:319–337.
Puelles L, Rubenstein JLR. 1993. Expression patterns of homeobox
and other putative regulatory genes in the embryonic mouse
forebrain suggest a neuromeric organization. Trends Neurosci 16:
472–476.
Puelles L, Verney C. 1998. Early neuromeric distribution of tyrosineimmunoreactive neurons in human embryos. J Comp Neurol 394:
283–308.
Rakic P. 1988. Specification of cerebral cortical areas. Science 241:170–
176.
Rakic P, Yakovlev PI. 1968. Development of the corpus callosum and
cavum septi in man. J Comp Neurol 132:45–72.
Robert O, Miachon S, Kopp N, Denoroy L, Tommasi M, Rollet D, Pujol
JF. 1984. Immunohistochemical study of the catecholaminergic
systems in the lower brain stem of the human infant. Human
Neurobiol 3:229–234.
Rosenberg DR, Lewis DA. 1995. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol
358:383–400.
Ruberg M, France-Lanord V, Brugg B, Lambeng N, Michel PP, Anglade
P, Hunot S, Damier P, Faucheux B, Hirsch E, Agid Y. 1997. La mort
neuronale par apoptose dans la maladie de Parkinson. Rev Neurol
153:499–508.
Sailaja K, Gopinath G. 1994. Developing substantia nigra in human: a
qualitative study. Dev Neurosci 16:44–52.
Saper CB, Petito CK. 1982. Correspondence of melanin-pigmented
neurons in human brain with A1-A14 catecholamine groups. Brain
105:87–101.
Schlumpf M, Shoemaker WJ, Bloom FE. 1980. Innervation of embryonic rat cerebral cortex by catecholamine-containing fibers. J Comp
Neurol 192:361–377.
Schwanzel-Fukuda M, Crossin KL, Pfaff DW, Bouloux PMG, Hardelin
J-P, Petit C. 1996. Migration of luteinizing hormone-releasing
hormone (LHRH) neurons in early human embryos. J Comp Neurol
366:547–557.
Shatz CJ, Chun JJM, Luskin MB. 1988. The role of the subplate in the
development of the mammilian telencephalon. In: Peters A, Jones
EG, editors. Cerebral cortex. New York: Plenum Press. p 35–58.
Shimamura K, Hartigan DJ, Martinez S, Puelles L, Rubenstein JLR.
1995. Longitudinal organization of the anterior neural plate and
neural tube. Development 121:3923–3933.
Sidman RL, Rakic P. 1973. Neuronal migration, with special reference
to developing human brain: a review. Brain Res 62:1–35.
Smeets WJAJ, Reiner A. 1994. Catecholamines in the CNS of vertebrates: current concepts of evolution and functional significance. In:
Smeets WJAJ, Reiner A, editors. Phylogeny and development of
catecholamine systems in the CNS of vertebrates. Cambridge:
Cambridge University Press. p 463–478.
Smeets WJAJ, Steinbusch HWM. 1990. New insights in the reptilian
catecholaminergic systems as revealed by antibodies against neurotransmitters and their synthetic enzymes. J Chem Neuroanat
3:25–43.
Smiley JF, Goldman-Rakic PS. 1993. Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial
section electron microscopy: a laminar analysis using the silverenhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. Cereb Cortex 3:223–238.
Smiley JF, Williams SM, Szigeti K, Goldman-Rakic PS. 1992. Light
and electron microscopic characterization of dopamine-immunoreactive axons in human cerebral cortex. J Comp Neurol 321:325–335.
Smith RL, Baker H, Kolstad K, Spencer DD, Greer CA. 1991.
Localization of tyrosine hydroxylase and olfactory marker protein
immunoreactivities in the human and macaque olfactory bulb.
Brain Res 548:140–148.
Specht LA, Pickel VM, Joh TH, Reis DJ. 1981. Light-microscopic
immunocytochemical localization of tyrosine hydroxylase in prenatal rat brain. I. Early ontogeny. J Comp Neurol 199:233–253.
Spencer S, Saper CB, Joh T, Reis DJ, Goldstein M, Raese JD. 1985.
Distribution of catecholamine-containing neurons in the normal
human hypothalamus. Brain Res 328:73–80.
Su HS, Peng ZC, Li YW. 1987. Distribution of catecholaminecontaining cell bodies in the human diencephalon. Brain Res
409:367–370.
Tillet Y. 1994. Catecholaminergic neuronal systems in the diencephalon of mammals. In: Phylogeny and development of catecholamine
systems in the CNS of vertebrates. In: Smeets WJAJ, Reiner A,
editors. Cambridge: Cambridge University Press. p 207–246.
Trottier S, Geffard M, Evrard B. 1989. Co-localization of tyrosinehydroxylase and GABA immunoreactivities in human cortical neurons. Neurosci Lett 109:76–82.
Ugrumov M. 1994. Hypothalamic catecholaminergic systems in ontogenesis: development and functional significance. In: Smeets WJAJ,
Reiner A, editors. Phylogeny and development of catecholamine
systems in the CNS of vertebrates. Cambridge: Cambridge University Press. p 435–452.
Ugrumov M, Proshlyakova E, Sapronova A, Popov A. 1996. Development of the mesencephalic and diencephalic catecholamine systems
in human fetuses: uptake and release of catecholamines in vitro.
Neurosci Lett 212:29–32.
Vaage S. 1969. Segmentation of the primitive neural tube in ckick
embryos. A morphological, histochemical and autoradiographic investigation. Adv Anat Embryol Cell Biol 41:1–88.
Van Domburg PHMF, Donkelaar HJT. 1991. The human substantia
nigra and ventral tegmental area. Adv Anat Embryol Cell Biol
121:1–131.
Verney C, Berger B, Adrien J, Vigny A, Gay M. 1982. Development of
the dopaminergic innervation of the rat cerebral cortex. A light
microscopic immunocytochemical study using anti-tyrosine hydroxylase antibodies. Dev Brain Res 5:41–52.
Verney C, Berger B, Baulac M, Helle KB, Alvarez C. 1984. Dopamineb-hydroxylase-like immunoreactivity in the fetal cerebral cortex of
the rat: noradrenergic ascending pathways and terminal fields. Int J
Neurosci 2:491–503.
Verney C, Alvarez C, Geffard M, Berger B. 1990. Ultrastructural
double-labelling study of dopamine terminals and GABA-containing
neurons in rat anteromedial cerebral cortex.Eur J Neurosci 2:960–
972
Verney C, Zecevic N, Nikovic B, Alvarez C, Berger B. 1991. Early
evidence of catecholaminergic cell groups in 5- and 6-old human
embryos using tyrosine-hydroxylase immunocytochemistry. Neurosci Lett 131:121–124.
Verney C, Zecevic N, Gaspar P, Berger B. 1992. Expression of calbindin
(CaBP) in human mesencephalic dopaminergic cells (A8-A9-A10.
from the 4th embryonic week on: immunocytochemistry of tyrosine
hydroxylase and CaBP. 7th International Catecholamine symposium, (Abstract).
Verney C, Milosevic A, Alvarez C, Berger B. 1993. Immunocytochemical evidence of well-developed dopaminergic and noradrenergic
innervations in the frontal cerebral cortex of human fetuses at
midgestation. J Comp Neurol 336:331–344.
Verney C, El Amraoui A, Zecevic N. 1996. Comigration of tyrosine
hydroxylase- and gonadotropin-releasing hormone-immunoreactive
neurons in the nasal area of human embryos. Dev Brain Res
97:251–259.
EMBRYONIC CATECHOLAMINERGIC NEURONS IN HUMANS
Versaux-Botteri C, Verney C, Zecevic N, Nguyen-Legros J. 1992. Early
appearance of tyrosine hydroxylase immunoreactivity in the retina
of human embryos. Dev Brain Res 69:283–287.
Vigny A, Henry JP. 1981. Bovine adrenal tyrosine hydroxylase:
comparative study of native and proteolysed enzyme and their
interaction with anions. J Neurochem 36:483–489.
Wang MZ, Jin P, Bumcrot DA, Marigo V, McMahon AP, Wang EA, Woolf T,
Pang K. 1995. Induction of dopaminergic neuron phenotype in the
midbrain by Sonic hedgehog protein. Nature Med 1:1184–1188.
Weinberger DR, Berman KF, Illowsky BP. 1988. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: III. A new
cohort and evidence for monoaminergic mechanism. Arch Gen
Psychiatry 45:609–615.
47
Yamada T, McGeer PL, Baimbridge KG, McGeer EG. 1990. Relative
sparing in Parkinson’s disease od substantia nigra dopamine neurons containing calbindin-D28k. Brain Res 526:303–307.
Zecevic N. 1993. Cellular composition of the telencephalic wall in
human embryos. Early Hum Dev 32:131–149.
Zecevic N, Verney C. 1995. Development of the catecholamine neurons
in human embryos and fetuses, with special emphasis on the
innervation of the cerebral cortex. J Comp Neurol 351:509–535.
Zecevic N, Bourgeois JP, Rakic P. 1989. Changes in synaptic density in
motor cortex of rhesus monkey during fetal and postnatal life. Dev
Brain Res 50:11–32.
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