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ORIGINAL ARTICLE
The receptor architecture of the pigeons’ nidopallium
caudolaterale: an avian analogue to the mammalian
prefrontal cortex
Christina Herold •Nicola Palomero-Gallagher •
Burkhard Hellmann •Sven Kro
¨ner •Carsten Theiss •
Onur Gu
¨ntu
¨rku
¨n•Karl Zilles
Received: 26 October 2010 / Accepted: 12 January 2011 / Published online: 4 February 2011
ÓSpringer-Verlag 2011
Abstract The avian nidopallium caudolaterale is a mul-
timodal area in the caudal telencephalon that is apparently
not homologous to the mammalian prefrontal cortex but
serves comparable functions. Here we analyzed binding-
site densities of glutamatergic AMPA, NMDA and kainate
receptors, GABAergic GABA
A
, muscarinic M
1
,M
2
and
nicotinic (nACh) receptors, noradrenergic a
1
and a
2
, sero-
tonergic 5-HT
1A
and dopaminergic D
1
-like receptors using
quantitative in vitro receptor autoradiography. We com-
pared the receptor architecture of the pigeons’ nidopallial
structures, in particular the NCL, with cortical areas Fr2
and Cg1 in rats and prefrontal area BA10 in humans. Our
results confirmed that the relative ratios of multiple
receptor densities across different nidopallial structures
(their ‘‘receptor fingerprints’’) were very similar in shape;
however, the absolute binding densities (the ‘‘size’’ of the
fingerprints) differed significantly. This finding enables a
delineation of the avian NCL from surrounding structures
and a further parcellation into a medial and a lateral part as
revealed by differences in densities of nACh, M
2
, kainate,
and 5-HT
1A
receptors. Comparisons of the NCL with the
rat and human frontal structures showed differences in the
receptor distribution, particularly of the glutamate recep-
tors, but also revealed highly conserved features like the
identical densities of GABA
A
,M
2
, nACh and D
1
-like
receptors. Assuming a convergent evolution of avian and
mammalian prefrontal areas, our results support the
hypothesis that specific neurochemical traits provide the
molecular background for higher order processes such as
executive functions. The differences in glutamate receptor
distributions may reflect species-specific adaptations.
Keywords Receptor autoradiography Prefrontal cortex
Nidopallium caudolaterale Rat Human Fr2 Cg1
BA10 Dopamine Glutamate GABA
Abbreviations
ACh Acetylcholine
AMPA a-Amino-3-hydroxy-5-methyl-4-isoxalone
propionic acid
Cg1 Cingulate cortex 1
CDL Dorsolateral corticoid area
EPSCs Excitatory postsynaptic currents
FR2 Frontal area 2
GABA c-Aminobutyric acid
GLI Gray level index
gluR1 Glutamate receptor subunit 1
HA Hyperpallium apicale
HVC Higher vocal center
IMM Intermediate and medial mesopallium ventrale
C. Herold (&)K. Zilles
C. and O. Vogt-Institute of Brain Research,
University of Du
¨sseldorf, 40225 Du
¨sseldorf, Germany
e-mail: christina.herold@uni-duesseldorf.de
N. Palomero-Gallagher K. Zilles
Institute of Neuroscience and Medicine INM-2,
Research Center Ju
¨lich, 52425 Ju
¨lich, Germany
B. Hellmann O. Gu
¨ntu
¨rku
¨n
Department of Biopsychology,
Institute of Cognitive Neuroscience,
Faculty of Psychology, Ruhr-University Bochum,
44780 Bochum, Germany
C. Theiss
Institute of Anatomy and Molecular Embryology,
Faculty of Medicine, Ruhr-University Bochum,
44780 Bochum, Germany
S. Kro
¨ner
School of Behavioral and Brain Sciences, The University
of Texas at Dallas, Richardson, TX 75080, USA
123
Brain Struct Funct (2011) 216:239–254
DOI 10.1007/s00429-011-0301-5
MNH Mediorostral nidopallium/hyperpallium
nACh Nicotinic acetylcholine
NCC Nidopallium caudocentrale
NCL Nidopallium caudolaterale
NCLl Nidopallium caudolaterale pars lateralis
NCLm Nidopallium caudolaterale pars medialis
NCM Nidopallium caudomediale
NFT Nidopallium fronto-trigeminale
NIM Nidopallium intermedium medialis
NMDA N-methyl-D-aspartate
PFC Prefrontal cortex
Introduction
The increasingly refined parcellation of the mammalian
cerebral cortex with anatomical methods enables various
analyses of its functional segregation (Uylings et al. 2000;
Amunts et al. 2004; Eickhoff et al. 2006, Amunts et al.
2007; Naito et al. 2008; Palomero-Gallagher et al. 2009;
Zilles and Amunts 2010). Similarly, in the last decades the
avian forebrain has been subdivided by various means.
These efforts have fostered a new understanding of the
avian telencephalic organization and the assumed homol-
ogies between avian and mammalian brain components
(Reiner et al. 2004). This new view, which is rooted in a
series of seminal studies over the last 40 years (Karten
1969), assumes that mammalian and avian pallia are
homologous in terms of shared pallial identity that derive
from common ancestry (Jarvis et al. 2005). This assump-
tion, however, does not imply that cortical or subcortical
pallial areas have to be one-to-one homologous to pallial
components in birds. Thus, pallial structures of birds and
mammals might be similar in terms of anatomical, physi-
ological and cognitive characteristics, but may still repre-
sent the result of convergent evolution.
The avian nidopallium caudolaterale (NCL) is such a
case. Numerous studies show that the mammalian pre-
frontal cortex (PFC) and the avian NCL share several
anatomical (Kro
¨ner and Gu
¨ntu
¨rku
¨n1999), neurochemical
(Bast et al. 2002; Karakuyu et al. 2007), electrophysio-
logical (Diekamp et al. 2002a; Kalenscher et al. 2005; Rose
and Colombo 2005), and functional (Gu
¨ntu
¨rku
¨n1997;
Diekamp et al. 2002b; Kalenscher et al. 2003; Lissek and
Gu
¨ntu
¨rku
¨n2005) characteristics; however, several genetic
(Puelles et al. 2000) and topological arguments (Medina
and Reiner 2000) make a homology between the PFC and
the NCL unlikely. Therefore, the similarities of these two
structures likely do not result from common ancestry but
represent the outcome of an evolutionary convergence.
Thus, a common selection pressure for an ‘executive’
behavioral repertoire possibly facilitates emergence of
non-homologous forebrain areas of mammals and birds that
share typical ‘prefrontal’ characteristics (Gu
¨ntu
¨rku
¨n2005a;
Kirsch et al. 2008).
The NCL displays a homogeneous cytoarchitecture and
does not differ considerably from neighboring portions of
the nidopallium either. The NCL was first defined by its
dopaminergic innervation and high tyrosine hydroxylase
density (Divac et al. 1985; Waldmann and Gu
¨ntu
¨rku
¨n
1993). To date, the outer borders and the internal structure
of the NCL have been analyzed with immunocytochemical
(Wynne and Gu
¨ntu
¨rku
¨n1995; Bock et al. 1997; Schnabel
et al. 1997; Durstewitz et al. 1998; Riters et al. 1999) and
ultrastructural methods (Metzger et al. 2002) as well as in
several tracing studies (Leutgeb et al. 1996; Metzger et al.
1998; Kro
¨ner and Gu
¨ntu
¨rku
¨n1999). Receptor autoradiog-
raphy is an additional powerful tool to define areal borders
and to derive region-specific receptor-density combinations
that define areas like ‘fingerprints’ (Zilles et al. 2002b).
Therefore, the first aim of this study was to map the
chemoarchitecture of the NCL. This approach is important
to define the areal borders between the nidopallium cau-
docentrale (NCC) and the NCL, since different studies
using tracing techniques or immunocytochemistry showed
discrepant delineations (Wynne and Gu
¨ntu
¨rku
¨n1995;
Waldmann and Gu
¨ntu
¨rku
¨n1993; Kro
¨ner and Gu
¨ntu
¨rku
¨n
1999; Atoji and Wild 2009). Although, the border to the
laterally and supraventricular located dorsolateral corticoid
area (CDL) and the NCL is easier to define, it was addi-
tionally included in the analysis here.
The second aim of this study was to investigate possible
subdivisions within the NCL because numerous studies in
mammals have implicated subdivisions of the PFC in the
processing of different stimulus domains (Levy and
Goldman-Rakic 1999). Similarly, there is also evidence for
a parcellation of the NCL based on functional, neuro-
chemical and hodological data (Leutgeb et al. 1996; Braun
et al. 1999; Kro
¨ner and Gu
¨ntu
¨rku
¨n1999; Riters et al. 1999;
Diekamp et al. 2002b). Riters et al. (1999) proposed a
dorsoventral distinction of the NCL based on the distri-
bution of tyrosine hydroxylase, choline acetyltransferase
and substance P labeled fibers and terminals. Accordingly,
lesions of the dorsal NCL result in delay-specific working
memory deficits (Diekamp et al. 2002b). The high density
of tyrosine hydroxylase positive fibers in the dorsal NCL
might be related to the important role of dopamine in
working memory functions as shown in primates (Goldman-
Rakic 1999) and birds (Karakuyu et al. 2007). Based on
connectivity data, however, Kro
¨ner and Gu
¨ntu
¨rku
¨n(1999)
assumed a frontocaudal distinction with the caudal portion
being tightly embedded within the limbic system.
The third aim was to compare the receptor fingerprints
of mammalian frontal and prefrontal areas with those of
the avian NCL in order to examine whether a common
240 Brain Struct Funct (2011) 216:239–254
123
functional repertoire is reflected by a similar pattern of
receptor architecture. For this purpose we studied the
receptor fingerprints of the medial and the lateral portions
of Brodmann’s human prefrontal cortex area BA10
(BA10m and BA10l, respectively) and the rat frontal area 2
(Fr2) as well as the rat prefrontal cingulate area 1 (Cg1)
(Brodmann 1909; Uylings et al. 2003). Owing to their
connectivity patterns with other neocortical areas, the
thalamus, the basal ganglia, and the amygdala, both Fr2
and Cg1 were structurally and functionally compared with
the dorsolateral prefrontal cortex in primates (Uylings et al.
2003; Van de Werd et al. 2010). However, it has to be
noted they there are still discrepancies in the delineations
of rat prefrontal and motor cortical structures; furthermore,
Fr2 is classified as the rodent’s motor cortex (Van Eden
et al. 1992; Zilles 1985).
Taken together, our receptor autoradiographic study was
aimed to constitute an independent approach to these open
questions.
Materials and methods
We examined a total of six pigeons (Columba livia)of
unknown sex and eight male rats (Long-Evans). Animals
were decapitated and the brains removed from the skull,
frozen immediately in isopentane at -40°C and stored at
-70°C. Serial coronal 10 lm sections were cut with a
cryostat microtome (2800 Frigocut E, Reichert-Jung).
Sections were thaw-mounted on gelatinized slides and
freeze-dried.
Post-mortem human brain tissue was studied from 2
control subjects (age 72 male and age 77 female, post-
mortem time 8 and 18 h) without a record of neurological
or psychiatric disorders and was obtained from the body
donor program of the Department of Anatomy, University
of Du
¨sseldorf, Germany. Causes of death were a heart
attack and carcinoma. Serial coronal cryosections (20 lm)
comprising the whole cross-section of unfixed brain blocks
were prepared at -20°C using a large-scale cryostat
microtome. Sections were thaw-mounted on gelatinized
slides, freeze-dried and stained with a modified cell
body staining for cytoarchitectonic analysis (Merker 1983;
Palomero-Gallagher et al. 2008) or processed for receptor
autoradiography.
Receptor autoradiography
Details of the autoradiographic labeling procedure have
been published elsewhere (Zilles et al. 2002b; Palomero-
Gallagher et al. 2009). Binding protocols are summarized
in Table 1. Three steps were performed in the following
sequence: (1) A preincubation step removed endogenous
ligand from the tissue. (2) During the main incubation step,
binding sites were labeled with triated ligand (total bind-
ing). Coincubation of the triated ligand and a 1,000 to
10,000-fold excess of an appropriate non-labeled ligand
(displacer) determined non-specific and thus non-dis-
placeable binding. Specific binding is the difference
between total and non-specific binding. (3) A final rinsing
step eliminated unbound radioactive ligand from the
sections.
The following binding sites were labeled according
to standardized protocols: a-amino-3-hydroxy-5-methyl-
4-isoxalone propionic acid (AMPA) with [
3
H] AMPA,
kainate with [
3
H]kainate, N-methyl-D-aspartate (NMDA)
with [
3
H]MK-801, c-aminobutyric acid A (GABA
A
) recep-
tor with [
3
H]muscimol, muscarinic cholinergic M
1
receptor
with [
3
H]pirenzepine, muscarinic cholinergic M
2
receptor
with [
3
H]oxotremorine-M, nicotinic cholinergic (nACh)
receptor with [
3
H]cytosine (pigeon) or [
3
H]epibatidine
(rat and human), noradrenergic a
1
adrenoreceptor with
[
3
H]prazosin, noradrenergic a
2
adrenoreceptor with [
3
H]
RX-821002, serotonergic 5-HT
1A
receptor with [
3
H]8-OH-
DPAT, and dopaminergic D
1
-like receptors with [
3
H]SCH
23390. Sections were air-dried overnight and subsequently
coexposed for 4–5 weeks against a tritium-sensitive film
(Hyperfilm, Amersham, Braunschweig, Germany) with
plastic [
3
H]-standards (Microscales, Amersham) of known
concentrations of radioactivity.
Image analysis
The resulting autoradiographs were subsequently processed
using densitometry with a video-based image analyzing
technique (Zilles et al. 2002b; Schleicher et al. 2005).
Autoradiographs were digitized by means of a KS-400
image analyzing system (Kontron, Germany) connected to
a CCD camera (Sony, Tokyo) equipped with a S-Ortho-
planar 60-mm macro lens (Zeiss, Germany). The images
were stored as binary files with a resolution of 512 9512
pixels and 8-bit gray value. The gray value images of the
coexposed microscales were used to compute a calibration
curve by non-linear, least-squares fitting, which defined the
relationship between gray values in the autoradiographs
and concentrations of radioactivity. This enabled the pixel-
wise conversion of the gray values of an autoradiograph
into the corresponding concentrations of radioactivity.
These concentrations of binding sites occupied by the
ligand under incubation conditions are transformed into
fmol binding site/mg protein at saturation conditions by
means of the equation: (K
D
?L)/A
S
9L, where K
D
is the
equilibrium dissociation constant of ligand-binding kinet-
ics, Lis the incubation concentration of ligand, and A
S
the
specific activity of the ligand. The mean of the gray values
contained in a specific region over a series of 4–5 sections
Brain Struct Funct (2011) 216:239–254 241
123
Table 1 Incubation conditions for receptor autoradiography
Receptor [
3
H] ligand
(incubation
concentration)
Displacer
(incubation
concentration)
Incubation buffer Preincubation
step
Main incubation step Rinsing step
AMPA [
3
H]AMPA (10 nM) Quisqualate
(10 lM)
50 mM Tris–acetate (pH 7.2) 3 910 min at
4°Cin
incubation
buffer
45 min at 4°C in incubation
buffer ?100 mM KSCN
494 s at 4°C in incubation
buffer ?292 s at 4°Cin
acetone/glutaraldehyde
Kainate [
3
H]kainate (8 nM) Kainate
(100 lM)
50 mM Tris–citrate (pH 7.1) 3 910 min at
4°Cin
incubation
buffer
45 min at 4°C in incubation
buffer ?10 mM Ca-acetate
494 s at 4°C in incubation
buffer ?292 s at 4°Cin
acetone/glutaraldehyde
NMDA [
3
H]MK-801
(5 nM)
MK-801
(100 lM)
50 mM Tris–HCl (pH 7.2) 15 min at 25°C
in incubation
buffer
60 min at 25°C in incubation
buffer ?30 lM
glycine ?50 lM spermidine
295 min at 4°C in incubation
buffer
Muscarinergic
cholinergic M
1
[
3
H]pirenzipine
(1nM)
Pirenzipine
(10 lM)
Modified Krebs–Ringer buffer (pH 7.4) 20 min at 25°C
in incubation
buffer
60 min at 25°C in incubation
buffer
295 min at 4°C in incubation
buffer
Muscarinergic
cholinergic M
2
[
3
H]oxotremonine-
M (0.8 nM)
Carbachol
(1 lM)
20 mM Hepes–Tris (pH 7.5)
?10 mM MgCl
2
20 min at 25°C
in incubation
buffer
60 min at 25°C in incubation
buffer
292 min at 4°C in incubation
buffer
Nicotinic
cholinergic
[
3
H]cytisine [1 nM] Nicotine
(10 lM)
50 mM Tris–HCl (pH7.4) ?120 mM
NaCl ?5 mM KCl ?1mM
MgCl
2
?2.5 mM CaCl
2
15 min at 22°C
in incubation
buffer
90 min at 4°C in incubation
buffer
292 min at 4°C in incubation
buffer
[
3
H]epibatidine
[0.5 nM]
Nicotine
(10 lM)
15 mM Hepes–Tris (pH 7.5) ?10 mM
NaCl ?5.4 mM KCl ?0.8 mM
MgCl
2
?1.8 mM CaCl
2
20 min at 22°C
in incubation
buffer
90 min at 4°C in incubation
buffer
195 min at 4°C in incubation
buffer
29up & down in distilled H
2
O
a
1
Adrenoreceptor
[
3
H]prazosin
(0.2 nM)
Phentolamine
(10 lM)
50 mM Tris–HCl (pH 7.4) 30 min at 37°C
in incubation
buffer
45 min at 30°C in incubation
buffer
295 min at 4°C in incubation
buffer
a
2
Adrenoreceptor
[
3
H]UK-14304
(1.4 nM)
Noradrenalin
(100 lM)
50 mM Tris–HCl (pH 7.7)
?100 lM MnCl
2
15 min at 22°C
in incubation
buffer
90 min at 22°C in incubation
buffer
5 min at 4°C in incubation buffer
GABA
A
[
3
H]muscimol
(6 nM:pigeon and
3 nM:human)
GABA
(10 lM)
50 mM Tris–citrate (pH 7.0) 3 95 min at
4°Cin
incubation
buffer
40 min at 4°C in incubation
buffer
393 s at 4°C in incubation buffer
Serotoninergic
5-HT
1A
[
3
H]8-OH-DPAT
(1 nM)
Serotonin
(10 lM)
170 mM Tris–HCl (pH 7.6) ?4mM
CaCl
2
?0.01% ascorbic acid
30 min at 22°C
in incubation
buffer
60 min at 22°C in incubation
buffer
195 min at 4°C in incubation
buffer
Dopaminergic
D
1
-like
[
3
H]SCH-23390
(0.5 nM)
SKF 83566
(1 lM)
50 mM Tris–HCl (pH 7.4) ?120 mM
NaCl ?5 mM KCl ?2 mM CaCl
2
?1 mM MgCl
2
?1lM mianserin
20 min at 22°C
in incubation
buffer
90 min at 22°C in incubation
buffer
2910 min at 4°C in incubation
buffer
242 Brain Struct Funct (2011) 216:239–254
123
from one animal is thus transformed into a receptor con-
centration (fmol/mg protein).
Anatomical identification
The borders of the NCL were identified based on previous
neurochemical (Waldmann and Gu
¨ntu
¨rku
¨n1993) and tract-
tracing studies (Kro
¨ner and Gu
¨ntu
¨rku
¨n 1998). The borders
of the NCL and surrounding structures as defined in the
atlas of Karten and Hodos (1967) were traced on prints of
the digitized autoradiographs. The borders of rat Fr2 and
Cg1 were anatomically identified based on a rat cortex atlas
(Zilles 1985). We decided to analyze these two regions
because they are assumed to be a part of the rat frontal and
prefrontal cortex (Uylings et al. 2003). The borders of
human BA10 were identified based on criteria defined by
Brodmann (Brodmann 1909). BA10m and BA10l were
additionally defined and traced onto digitized autoradio-
graphs (n=3 hemispheres). The mean of the gray values
contained in a specific region over a series of 4–5 sections
from one hemisphere is thus transformed into a receptor
concentration per unit protein (fmol/mg protein).
Statistical analysis
To investigate the chemoarchitectural differences between
the NCL and the surrounding structures, the binding site
concentrations of the NCL were compared with those of
the nidopallium caudomediale (NCM, located medial to
NCL) and the dorsolateral corticoid area (CDL, located
dorsolaterally to NCL, above the ventricle). First, a
Friedman ANOVA was conducted. If significant, pair wise
comparisons were run with the Wilcoxon rank test. Binding
site concentrations of the NCM were measured medial to
Field L. Differences between nidopallium caudolaterale
pars medialis (NCLm) and nidopallium caudolaterale pars
lateralis (NCLl) were further analyzed with Wilcoxon rank
tests.
Results
Receptor-binding site densities in avian pallial
structures
The most caudal portion of the avian nidopallium displays
a rather homogeneous cytoarchitecture. The only subven-
tricular cytoarchitectural feature that is clearly different
from the otherwise homogeneous pattern is Field L in the
most medial part. Within Field L, especially, the granular
layer L2 is readily visible. Ventrolaterally, the lamina
arcopallialis dorsalis defines the borderline between the
nidopallium and the arcopallial and the amygdalar
substructures. Dorsally, the caudal cap of the lateral ven-
tricle separates the nidopallium from the CDL and the
hippocampal and parahippocampal structures. The distri-
bution of different ligand-binding sites shows that the
cytoarchitectonically seemingly homogeneous caudal nid-
opallium is in fact comprised of several substructures.
Further, the examined receptor types not only enabled a
clear delineation of the NCL from the adjoining areas, but
also revealed the existence of two hitherto unknown sub-
entities. Stereotaxic coordinates, A 5.50 and A 6.75, were
chosen as exemplary levels for which all receptor types
were shown in Fig. 1a and b. Different binding-site den-
sities within the borders of the NCL could be followed up
to the most caudal aspect of the subventricular forebrain
where it constituted the most caudal tip of the nidopallium.
Frontally, the NCL was visible up to A 7.50 (anterior–
posterior coordinates according to the pigeon brain atlas of
Karten and Hodos 1967). Further, binding-site densities of
the different receptor ligands are presented relative to each
other in a 2-dimensional coordinate plot to construct
a receptor fingerprint for a given brain area (Fig. 2).
This allows us to compare the shape and the absolute size
of this receptor fingerprint across brain areas and between
species.
As illustrated in the autoradiographs and in the finger-
prints, glutamatergic AMPA and NMDA receptors show
the highest densities of all measured receptors, and were
followed by GABA
A
receptor densities. Conversely, lowest
values were found for nACh, a
1
and D
1
-like receptor
densities (Figs. 1a/b, 2a).
The mean density of AMPA receptors for the whole
NCL was 2,252 ±269 fmol/mg protein. A comparison of
binding densities between NCL, NCC and CDL using a
Friedman ANOVA showed no significant overall effects
[Chi Square (N=6, df =2) =1, n.s.].
Overall densities for kainate receptor-binding sites were
660 ±81 fmol/mg (Fig. 1a/b). Because kainate receptor-
binding sites were approximately fivefold lower than those
of AMPA receptors, and sixfold lower than those of
NMDA receptors, this resulted in a considerable indenta-
tion in the fingerprint (Fig. 2a). Binding of [
3
H]kainate was
highest in the most lateral portion of the NCL (Figs. 1a/b,
3). We labeled this area nidopallium caudolaterale pars
lateralis (NCLl) to differentiate it from the medial portion
of the NCL (NCLm). The Friedman ANOVA showed a
significant overall effect [Chi Square (N=6, df =2) =
10.33, p\0.01]. Binding was higher both in NCL and
NCC than in CDL (all N=6, T=0, p\0.05). Addi-
tionally, a significant higher concentration of kainate
receptors in the lateral than in the medial aspect of the NCL
was detected (N=6, T=1, p\0.05; Fig. 3).
Binding of [
3
H]MK-801 was very high throughout the
entire caudal nidopallium (Fig. 1a/b), indicating a high
Brain Struct Funct (2011) 216:239–254 243
123
density of NMDA receptors. Binding density reached
2,525 ±143 fmol/mg protein (Figs. 1a, 2a) in NCL. Like
for the AMPA receptors this results in a prominent peak in
the fingerprints (c.f Fig. 2a). The Friedman ANOVA
comparing NCL, NCC and CDL showed a significant
overall effect [Chi Square (N=6, df =2) =8.33,
p\0.05]. A subsequent Wilcoxon test revealed signifi-
cantly higher values for NCL and NCM over CDL (all
N=6, TB1, p\0.05).
GABA
A
receptor-binding sites were labeled with
[
3
H]muscimol (mean density 1,810 ±188 fmol/mg pro-
tein). Since binding increased medial to NCC, the border of
the NCL could be easily visualized (Fig. 1a/b). The Fried-
man ANOVA showed a significant main effect [Chi Square
(N=6, df =2) =12, p\0.005]. Subsequent Wilcoxon
tests revealed a significantly stepwise decrease of binding
from NCC over NCL to CDL (all N=6, T=0, p\0.05)
that is particularly illustrated in the fingerprints (Fig. 2a).
The study of binding sites for the neurotransmitter
acetylcholine revealed low densities for all analyzed cho-
linergic receptors. Binding of [
3
H]pirenzepine to muscari-
nergic cholinergic receptors of the M
1
-type was very low in
the caudolateral nidopallium (NCL: 151 ±24 fmol/mg
protein; Figs. 1a/b, 2a). A further differentiation within
NCL was not visible. The Friedman ANOVA using the
data from NCL, NCC and CDL showed a significant
overall effect [Chi Square (N=6, df =2] =6.52,
p\0.05). Subsequent Wilcoxon tests revealed that the
concentration was significantly lower in NCL compared to
both NCC and CDL (N=6, TB1, p\0.05; Fig. 2).
M
2
-receptors presented the highest densities of all
determined cholinergic receptors in the nidopallial struc-
tures (269 ±39 fmol/mg protein; Fig. 2a). The Friedman
ANOVA comparing NCL, NCC and CDL showed a
significant overall effect [Chi Square (N=6, df =2) =
10.33, p\0.01). Subsequent Wilcoxon tests revealed a
Fig. 1 Color-coded autoradiographs showing the distribution of
AMPA, kainate, NMDA, GABA
A
,M
1
,M
2
, nicotinic cholinergic
(nACh), a
1
,a
2
, 5-HT
1A
and D
1
-like receptors in coronal sections
through the pigeon brain at rostrocaudal levels A 5.50 (a) and A 6.75
(b). Extent of the NCL at each of these levels is highlighted in gray in
the schematic drawing. Scale bars code for receptor densities in fmol/
mg protein
244 Brain Struct Funct (2011) 216:239–254
123
significantly stepwise increase of binding strength from
CDL over NCL to NCM (N=6, TB1, p\0.05) and a
parcellation of NCLm and NCLl (N=6, T=0, p\0.05;
Fig. 3).
Binding of [
3
H]cytisine to nicotinic receptors was very
low in the whole lateral aspect of the nidopallium
(144 ±12 fmol/mg protein, Fig. 1a/b and Fig. 2a), indi-
cating low densities of nACh receptors (Fig. 2a). The
Friedman ANOVA showed a significant overall effect [Chi
Square (N=6, df =2) =12, p\0.005]. Subsequent
Wilcoxon tests revealed a significantly stepwise decrease
of binding strength from CDL over NCL to NCC (N=6,
T=0, p\0.05). Further, binding densities between
NCLm and NCLl differed significantly (N=6, T=0,
p\0.05; Fig. 3).
The noradrenergic a
1
receptor was visualized by means
of [
3
H]prazosin (127 ±16 fmol/mg protein; Fig. 1a/b).
Although in few cases the ventral aspect of the NCL,
abutting the arcopallium, displayed some higher binding,
this was not consistently observed. A differentiation
between NCLl and NCLm was not evident. The Friedman
ANOVA comparing NCL, NCC and CDL showed a sig-
nificant overall effect [Chi Square (N=6, df =2) =12,
p\0.005]. Subsequent Wilcoxon tests revealed a signifi-
cantly stepwise decrease of binding strength from CDL
over NCL to NCC (all N=6, T=0, p\0.05; Fig. 2a).
[
3
H]RX821002 binds to noradrenergic a
2
receptor and
displayed moderate binding in NCL (308±27 fmol/mg
protein). Substructures within the NCL were not visible
(Fig. 1a/b). The Friedman ANOVA showed a significant
overall effect [Chi Square (N=6, df =2) =9.33,
p\0.01]. Subsequent Wilcoxon tests revealed that bind-
ing in NCC was significantly higher than both in NCL and
CDL (all N=6, T=0, p\0.05; Fig. 2).
Serotonergic 5-HT
1A
receptor-binding sites were visu-
alized with [
3
H]8-OH-DPAT. NCL revealed lower densi-
ties (374 ±67 fmol/mg protein) than the medially abutting
nidopallial areas, again providing the possibility to clearly
identify the medial wall of the NCL (Fig. 1a/b). The
Friedman ANOVA showed a significant overall effect
Fig. 1 continued
Brain Struct Funct (2011) 216:239–254 245
123
[Chi Square (N=6, df =2] =12, p\0.005). Sub-
sequent Wilcoxon tests revealed a significantly stepwise
increase of binding strength from CDL over NCL to NCC
(all N=6, T=0, p\0.05, Fig. 2a). Furthermore,
5-HT
1A
receptors were more abundant in NCLm than
NCLl (N=6, T=0, p\0.05; Fig. 3).
[
3
H]SCH23390 was used to reveal the location and
density of dopaminergic D
1
-like receptors. Ligand bind-
ing was mainly concentrated within the NCL without
showing a difference between the lateral and the medial
component (Fig. 1a/b). Although density in NCL was
rather low (92 ±12 fmol/mg protein), a Friedman
ANOVA comparing NCL, NCC, and CDL showed a
significant overall effect [Chi Square (N=6, df =2) =
12, p\0.01]. A subsequent Wilcoxon test revealed sig-
nificantly higher values for NCL and CDL over NCC
(N=6, T=0, p\0.05; Fig. 2) as well as significantly
higher values for NCL than for CDL (N=6, T=0,
p\0.05; Fig. 2).
Based on the different binding site densities for kai-
nate, NMDA, GABA
A
,M
1
,M
2
, nACh, a
1
,a
2
, 5-HT
1A
and
D
1
-like receptors a detailed outline of the NCL is depicted
in Fig. 4.
Comparison of receptor-binding site densities
in the avian NCL to mammalian prefrontal structures
In the rat (Fig. 2b) and human (Fig. 2c) prefrontal areas
examined, AMPA and GABA
A
receptors showed the
highest densities of all measured receptor types, and were
followed by NMDA receptor densities (Fig. 2b/c). Lowest
values were found for nACh, and D
1
-like receptor
densities.
Human and rat prefrontal areas differed considerably in
their relative balance of ionotropic glutamatergic receptors.
In human areas, BA10l and BA10m, kainate receptor
densities were comparable to those of AMPA receptors,
and only slightly lower than those of NMDA receptors
(Fig. 2c). In rat areas, Fr2 and Cg1, similar to the situation
described for the pigeon nidopallial areas, kainate receptor
Fig. 2 Receptor fingerprints for CDL, NCL, NCC of the pigeon
pallium (a), for Fr2 and Cg1 of the rat cortex (b) and for the BA10l
and BA10m of the human cortex (c). The mean densities (fmol/mg
protein) of glutamatergic (AMPA, kainate, NMDA), GABAergic
(GABA
A
), acetylcholinergic muscarinic (M
1
,M
2
) and nicotinic
(nACh), adrenergic (a
1
,a
2
), serotonergic (5-HT
1A
) and dopaminergic
(D
1
-like) receptors are displayed in polar coordinate plots. The lines
connecting the mean densities define the shape of the fingerprint
based on 11 different binding sites for each area. Note that the scales
in a–care different. BA10l Brodmann area 10 lateral, BA10m
Brodmann area 10 medial, CDL area corticoidea dorsolateralis, NCL
nidopallium caudolaterale, NCC nidopallium caudocentrale, Fr2
frontal area 2, Cg1 cingulate cortex 1
b
246 Brain Struct Funct (2011) 216:239–254
123
densities were considerably lower than those of AMPA
(fourfold lower) or NMDA (five to sixfold lower) receptor
densities (Fig. 2b). Thus, the pigeon and rat, but not the
human fingerprints presented a conspicuous indentation at
the level of the kainate receptors.
The examined human and rat prefrontal areas presented
the same balance of cholinergic receptor densities, with
highest concentrations for the muscarinic M
1
cholinergic
type and lowest values for the nicotinic receptor (Fig. 2b/
c). This pattern differs however, from that of pigeons, since
nidopallial areas contain higher M
2
than M
1
receptor
densities (Fig. 2a).
In the group of monoaminergic receptors, noradrenergic
a
1
receptor densities were higher than those of a
2
receptors
in both human and rat prefrontal areas (Fig 2b/c). Con-
versely, a
1
receptor densities were lower than of a
2
receptor densities in the pigeon nidopallium (Fig. 2a).
Serotoninergic 5-HT
1A
receptor densities were higher than
those of a
1
receptors in human areas BA10l and BA10m,
whereas the opposite holds true for rat areas Fr2 and Cg1
(Fig. 2b/c). D
1
-like binding-site densities showed neither
differences between the analyzed prefrontal structures nor
the pigeon’s NCL (Fig. 2b/c).
Discussion
Using a quantitative analysis of 11 different receptor-
binding sites, the present study aimed to (1) analyze the
areal borders of the constituents of the caudolateral part of
the pigeons’ telencephalon, (2) to reveal possible subdivi-
sions within the NCL, (3) to compare the receptor finger-
prints of NCL and the surrounding NCC and CDL with
those of frontal areas in mammals.
Fig. 3 Histogram of the mean
receptor densities (fmol/mg
protein) of the pigeon’s areas
NCLm and the NCLl. Error
bars represent standard
deviations. Asterisks indicate
significant differences between
receptor densities
Fig. 4 Atlas of the NCL in serial frontal sections based on different receptor densities. The length of the bar represents 3 mm
Brain Struct Funct (2011) 216:239–254 247
123
Areal delineation in the pigeons’ caudolateral
telencephalon
Moving from centromedial to lateral, the avian caudolat-
eral telencephalon is constituted by the three areas: NCC,
NCL, and CDL. The NCC receives its input predominantly
from the dorsal intermediate mesopallium and projects to
arcopallial subfields. The arcopallial outflow to the medial
hypothalamus could imply that NCC is involved in neu-
roendocrine and autonomic functions and is limbic in
nature (Yamamoto and Reiner 2005; Atoji and Wild 2009).
The interconnectivity between NCC and NCL seems to be
surprisingly weak (Atoji and Wild 2009; Kro
¨ner and
Gu
¨ntu
¨rku
¨n1999). Further, the pattern of afferents and
efferents of NCC and NCL is considerably different
(Leutgeb et al. 1996; Metzger et al. 1998; Kro
¨ner and
Gu
¨ntu
¨rku
¨n1999; Atoji and Wild 2009). Thus, although
NCC and NCL cannot be delineated by cytoarchitectonic
means and were subsumed into area Ne16 in the quanti-
tative cytoarchitectonic study of Rehka
¨mper and Zilles
(1991), they show marked differences in hodology. The
study of Atoji and Wild (2009) placed the borderline
between NCC and NCL far more laterally than the
immunocytochemical and connectivity analyses conducted
on the NCL (Waldmann and Gu
¨ntu
¨rku
¨n1993; Leutgeb
et al. 1996; Kro
¨ner and Gu
¨ntu
¨rku
¨n1999; Riters et al.
1999). In fact, according to Atoji and Wild (2009), NCLm
would be part of NCC. Interestingly, the reconstruction of
the location of retrogradely labeled neurons in Atoji and
Wild (2009) reveals a border that is more close to that of
the present study and similar to the original delineation by
Waldmann and Gu
¨ntu
¨rku
¨n(1993) and this is reflected by
the distribution patterns of a
1
, 5-HT
1A
and D
1
-like recep-
tors. However, the caudal aspect of the avian nidopallium
is organized in clusters with fuzzy borders; in addition, not
all receptor-binding sites defined clear boundaries between
areas. Thus, the distribution patterns of the receptors con-
firm a smooth transition at the caudal site and both areas
probably do not have a clear boundary at that point.
Therefore, in the most caudal portion of the nidopallium,
the delineation between NCC and NCL becomes extremely
difficult and may have led to different findings in the past
(Atoji and Wild 2009).
Towards the lateral border, the distinction between NCL
and CDL is easy due to the ventricle that separates these
two areas. The CDL is considered to be mostly limbic in
nature and was hodologically compared to the mammalian
cingulate cortex (Yamamoto and Reiner 2005; Atoji and
Wild 2005; Csillag and Montagenese 2005). It shares
similarities with the receptor architecture of the hippo-
campal formation (data not shown) and nidopallial struc-
tures. CDL extents rostrally up to A 6.75 where NCL and
CDL are no longer separated by the lateral ventricle but
directly abut each other. At this point, the autoradiographic
data revealed a less fuzzy transition when compared to the
caudal aspects of NCL and NCC, depicting that NCL fol-
lows the outer curvature of the telencephalon but always
stays about 1 mm away from the pial surface. Similarly,
the rostral border of the NCL is easier to define as it tapers
up to A 7.50.
Subdivisions of the NCL
Our findings reveal a clear parcellation of the avian nid-
opallium that is in line with tracing studies (Rehka
¨mper
and Zilles 1991; Leutgeb et al. 1996; Kro
¨ner and Gu
¨ntu
¨r-
ku
¨n1999; Atoji and Wild 2009). Earlier studies have
shown functional and neurochemical subdivisions of the
NCL (Leutgeb et al. 1996; Braun et al. 1999; Kro
¨ner and
Gu
¨ntu
¨rku
¨n1999; Riters et al. 1999). Here, a new subdi-
vision into a medial and a lateral part is proposed by the
differences of the mean receptor densities of nACh, M
2
,
kainate, and 5-HT
1A
receptors. Some earlier tracing and
neurochemical studies revealed a possible dorsal and ven-
tral component (Leutgeb et al. 1996; Braun et al. 1999;
Riters et al. 1999). The neurochemical subdivision into a
dorsal and a ventral component also coincides with hod-
ological data showing that only dorsal NCL receives
afferents from multimodal thalamic nuclei (Korzeniewska
and Gu
¨ntu
¨rku
¨n1990;Gu
¨ntu
¨rku
¨n and Kro
¨ner 1999) and
contributes more significantly to working memory perfor-
mance (Diekamp et al. 2002a,b). Dorsal, but not ventral
NCL, is connected with a complex of association structures
in the rostromedial nidopallium and ventral hyperpallium
in different species of birds. In domestic chicken two
extensively overlapping structures, the mediorostral nid-
opallium/hyperpallium (MNH) and the intermediate and
medial mesopallium ventrale (IMM), play a pivotal role in
auditory and visual filial imprinting, respectively (Horn
1981; Braun et al. 1999). These areas are activated during
imprinting and lesions cause deficits in recognizing the
imprinting stimulus (Horn 1981; Horn et al. 1985). In
chicken, IMM is also a nodal point of initial memory
formation in one-trial passive avoidance learning with
gustatory cues (Rose 2000). Both MNH and IMM project
to dorsomedial NCL as shown in chicken (Metzger et al.
1998) and pigeons (Kro
¨ner and Gu
¨ntu
¨rku
¨n1999). How-
ever, we could not confirm a border between dorsal and
ventral NCL based on the receptor-density profiles. On the
other hand, Kro
¨ner and Gu
¨ntu
¨rku
¨n(1999) demonstrated
that the component labeled NCLl in our preparations
receives input from secondary areas of sensory represen-
tation and projects back to these structures. Furthermore, a
large number of neurons from NCL projects to the arco-
pallium and these output neurons are close to the densest
catecholaminergic innervations that are located in the
248 Brain Struct Funct (2011) 216:239–254
123
lateral part of the NCL (Waldmann and Gu
¨ntu
¨rku
¨n1993;
Kro
¨ner and Gu
¨ntu
¨rku
¨n1999). In addition, a large number
of medial NCL neurons project to the basal ganglia in
pigeons (Veenman et al. 1995; Kro
¨ner and Gu
¨ntu
¨rku
¨n
1999). Therefore, NCLl displayed a different connectivity
pattern from NCLm. Due to the curvature of the NCL,
NCLl is positioned more dorsally than NCLm. Thus, a
dorsoventral subdivision of the NCL could mistakenly be
concluded from the lateromedial differentiation of a
semilunar structure.
The neurochemistry of the caudolateral avian forebrain
In NCL, NCC, and CDL the highest receptor densities were
detected for glutamatergic and GABA
A
receptors. This is
in line with earlier studies that determined receptor levels
in the nidopallium of various bird species (Dietl and
Palacios 1988; Stewart et al. 1988,1999; Mitsacos et al.
1990; Aamodt et al. 1992; Veenman et al. 1994; Ben-Ari
et al. 1997; Salvatierra et al. 1997). Pigeons showed higher
AMPA and NMDA receptor concentrations in the nid-
opallium when compared to other birds, while the amount
of GABA
A
receptor densities seemed to be similar in
pigeons, chicks and zebra finches (Stewart et al. 1988;
Henley and Barnard 1990; Veenman et al. 1994; Martinez
de la Torre et al. 1998; Stewart et al. 1999; Pinaud and
Mello 2007). The present study reports for the first time
kainate receptor densities in the pigeon’s pallium. If
compared to AMPA and NMDA receptors, kainate binding
was about four times lower in all of the above-mentioned
structures. However, like for the NMDA receptors, kainate
binding differed between the CDL and the nidopallial
structures, showing a clear segregation. This is in line with
an immunohistochemical study in quails, showing that
AMPA and NMDA receptors have higher densities than
kainate receptors in the nidopallium. In addition, kainate
and NMDA binding is lower in the CDL while the AMPA
receptor subunit GluR1 was intensely labeled in the CDL
(Cornil et al. 2000). Binding of the GABA
A
receptor also
increased from the surface to the deeper nidopallial areas,
confirming earlier immunohistochemical und receptor
autoradiographic studies (Rehka
¨mper and Zilles 1991;
Veenman et al. 1994). In the nidopallium, cholinergic
muscarinic and nicotinic receptors showed an intermediate
to low density, which is in line with results from other
studies of muscarinic or nicotinic binding sites in the tel-
encephalon of pigeons, chicks, quails, sparrows, and star-
lings (Dietl et al. 1988; Ball et al. 1990; Sorenson and
Chiappinelli 1992). As described for the GABA
A
receptor,
the M
2
receptor density increases from the superficial CDL
over the NCL to the NCM while the nACh receptor den-
sities decreases. The boundaries of the NCL were revealed
by all cholinergic receptors.
The monoaminergic receptors were differentially dis-
tributed. Their densities ranged from very low (D
1
-like
receptors) to moderate (5-HT
1A
receptors). Densities of the
a
2
receptors varied across different bird species in the CDL
and in the nidopallium (Balthazart and Ball 1989; Ball
et al. 1995; Diez-Alarcia et al. 2006). To our knowledge to
date no specific information about the densities of 5-HT
1A
receptor densities is available on the avian pallium,
although it was shown in a competition assay with [
3
H]5-
HT binding that 5-HT
1A
receptors were abundant in the
pigeon’s telencephalon (Waeber et al. 1989). Comparable
results were reported for the D
1
-like receptor in the nid-
opallium of pigeons (Dietl and Palacios 1988).
Comparison to mammals and functional considerations
As first shown by lesion experiments (Mogensen and
Divac 1982), the NCL is involved in executive functions.
More recent studies have confirmed that the NCL shares
many similarities with the mammalian prefrontal cortex
(Gu
¨ntu
¨rku
¨n, 2005a,b; Kirsch et al. 2008). These findings
can be seen in parallel to observations in corvids and
parrots which possess cognitive abilities that are compa-
rable to those of monkeys and apes (Bird and Emery 2010;
Hunt and Gray 2003; Emery and Clayton 2004; Kenward
et al. 2005; Seed et al. 2006; Prior et al. 2008; Taylor et al.
2009; Pollok et al., 2000). As observed for other mammals
(Harvey and Krebs 1990) this is accompanied by an
increased encephalization (Cnotka et al. 2008) and a rela-
tive growth of associative forebrain areas (Mehlhorn et al.
2010). Based on topographical and genetic arguments both
the NCL and the prefrontal cortex seem to be a case of
homoplasy (Puelles et al. 2000). Additionally, the mor-
phological organization of avian and mammalian fore-
brains differs importantly, with the avian pallium having a
nuclear organization while the mammalian dorsal pallium
assumes a laminar structure. Thus, a layered cortical
structure appears not to be a prerequisite for higher cog-
nitive functions (Kirsch et al. 2008). In contrast to the
NCL, less is known about the CDL and its functions. The
connections of the avian CDL share similarities with those
of the mammalian cingulate cortex (Vogt and Pandya
1987; Atoji and Wild 2005). Neurobehavioral studies in
which the CDL was lesioned as part of larger lesions to the
lateral nidopallium or the hippocampal formation indicate
a role for the CDL in spatial memory (Hartmann and
Gu
¨ntu
¨rku
¨n1998; Bingman et al. 1985; Colombo et al.
2001; Gagliardo et al. 2001). Only one study showed that
CDL lesions did not impair performance in simultaneous
pattern or delayed alternation discrimination tasks
(Gagliardo et al. 1996). Receptor autoradiography and
receptor fingerprints of brain regions provide a tool to
compare the chemoarchitecture between different species.
Brain Struct Funct (2011) 216:239–254 249
123
Therefore, our results will be further discussed in the light
of comparative studies in birds, primates and rats.
As in the pigeon’s NCL and CDL, high receptor den-
sities for glutamatergic and GABAergic receptors were
found in the prefrontal regions investigated here, as well as
in other cortical regions of rats, monkeys and humans
(Gebhard et al. 1995; Geyer et al. 1998; Zilles et al. 2002a,
b; Palomero-Gallagher and Zilles 2004). However, there
were differences in the amount of distinct glutamate
receptors between species. AMPA and NMDA receptors
showed high concentrations in the NCL and the CDL of
pigeons and chicks (Bock et al. 1997) if compared to
frontal structures of mammals. Kainate receptors seemed to
be very low in rat FR2 and Cg1, while they did not differ
substantially between human BA10 and the NCL, and
between the CDL and the human cingulate cortex (Palo-
mero-Gallagher et al. 2009). By contrast, the amounts of
GABA
A
receptors were equally distributed in the prefrontal
areas of all the investigated species here and also in the
NCL of pigeons and chicks (Stewart et al. 1988). The same
is true for the CDL and the human as well as the macaque
cingulate cortex (Bozkurt et al. 2005; Palomero-Gallagher
et al. 2009). Thus, there seems to be a shift towards higher
densities of glutamate receptors in avian nidopallial
structures. Therefore, the top right quadrant of the finger-
prints for the birds’ nidopallial structures differs in size
when compared to the rodent frontal areas, and differ in
shape for both species, if compared to human BA10.
Cholinergic M
1
receptors were highest in human if
compared to macaque monkey, rhesus monkey, rat and
pigeon, while M
2
and nicotinic receptors showed equal
densities (Bozkurt et al. 2005; Lidow et al. 1989). How-
ever, pigeons showed an inverted pattern of M
1
/M
2
binding
if compared to other species. ACh is an essential regulator
of cortical excitability and plays important roles for arou-
sal, attention, and cognitive processes (Sarter and Bruno
2000; Hasselmo and Stern 2006; Briand et al. 2007; Sarter
et al. 2009). These functions are mediated by muscarinic
and nicotinic ACh receptors. In the cerebral cortex the M
1
receptor is preferentially expressed in pyramidal cells and
enriched on the extrasynaptic membrane of their dendrites
and spines (Yamasaki et al. 2010). The M
2
receptor is the
primary muscarinic autoreceptor presynaptically regulating
ACh release in the forebrain of rodents and primates
including humans (Mrzljak et al. 1995; Zhang et al. 2002).
Both receptor subtypes are metabotropic. M
1
couples to a
stimulatory G-protein whereas M
2
couples to an inhibitory
G-protein. Genetic variation of the CHRM2 gene encoding
the M
2
receptor selectively influence muscarinic presyn-
aptic inhibition (Comings et al. 2003). The nACh receptors
are fast-acting ligand-gated ion channels producing EPSPs.
A recent genetic approach showed that both, fast-acting
nicotinic receptors and slow-acting muscarinic receptors
influence in a synergistic system the efficiency of shifting
visuospatial attention in the PFC (Greenwood et al. 2009).
In pigeons, central cholinergic systems are important for
temporal memory processes and spatial orientation during
homing, two processes that also involve the NCL
(Gagliardo and Divac 1993; Santi and Weise 1995; Kohler
et al. 1996; Riters and Bingman 1999).
Like for the muscarinic cholinergic receptors, the same
inverted ratio was detected in the NCL and in the CDL for
the noradrenergic a
1
and a
2
receptors if compared to pre-
frontal or cingulate structures in mammals. In humans,
macaque monkeys and rats higher amounts of a
1
than of a
2
receptors were described (Goldman-Rakic et al. 1990;
Bozkurt et al. 2005; Palomero-Gallagher et al. 2009). Both
receptor types are metabotropic and a
1
receptors are cou-
pled to stimulatory G-proteins, while a
2
receptors are
coupled to inhibitory G-proteins. In the PFC of monkeys,
a
2
receptors are located postsynaptically at the dendritic
spines of pyramidal neurons where glutamate receptors are
concentrated (Aoki et al. 1998). Behavioral pharmacolog-
ical studies in rodents, monkeys, and humans demonstrated
that systemically or locally administered a
2
receptor ago-
nists could improve PFC cognitive performances (Robbins
and Arnsten 2009). Further, it was shown that stimulation
of a
2
receptors suppresses glutamate synaptic transmission
in the PFC and tunes the synaptic output to an optimal state
for working memory function (Wang et al. 2007; Ji et al.
2008). In songbirds noradrenalin is involved in song
learning at different developmental stages by controlling
local circuits in the higher vocal center (HVC) (Fortune
and Margoliash 1995) and modulation of auditory
responses through attention processes (Castelino and
Schmidt 2010). The HVC could be an oscine specialization
of the dorsal NCL (Farries 2001). Because both the M
1
/M
2
and the a
1
/a
2
ratio show an inverted pattern in the NCL
resulting in an increased inhibitory control on local circuits
this may be a compensating mechanism for the shift to
glutamatergic processing.
The densities of 5-HT
1A
receptors were equal in the
prefrontal areas of humans, monkeys and pigeons, while
rats showed lower densities (Goldman-Rakic et al. 1990).
The 5-HT
1A
subtype is of particular interest, since it is one
of the main mediators of 5-HT and contributes to a lot of
prefrontal functions (Sakaue et al. 2000; de Almeida et al.
2008). In the human cingulate cortex the density of the
5-HT
1A
subtype is slightly higher than in the CDL (Palo-
mero-Gallagher et al. 2009). In birds less is known about
the serotonergic contribution to executive functions, but it
was shown that serotonin release was increased in the NCL
during a working memory task (Karakuyu et al. 2007).
D
1
-like receptors showed the lowest densities of all
measured receptor types in the assumed prefrontal and
cingulate regions of pigeons, rats, monkeys, cats, tree
250 Brain Struct Funct (2011) 216:239–254
123
shrews and humans (Richfield et al. 1989; Goldman-Rakic
et al. 1990; Palomero-Gallagher et al. 2009). In mammals,
low densities of D
1
-like receptors in frontal areas are
associated with volume transmission of dopamine and a
diffuse action of dopamine on multiple components of
cortical networks (reviewed in Gonzalez-Burgos et al.
2007). These results also reveal that the dopaminergic
system seems to be highly conserved across species,
although prefrontal structures evolved independently
(Callier et al. 2003). Thus, the dopaminergic system and its
interactions with other systems might constitute a key
element for our understanding of the anatomical/chemical
traits that are necessary for proper executive functions. The
low density of D
1
-like receptors might also explain why
species share similar deficits if signaling via this receptor-
type is disturbed (Zahrt et al. 1997; Williams and Castner
2006; Herold et al. 2008; McNab and Klingberg 2008;
Rose et al. 2010).
In summary, it appears that the GABAergic and dopa-
minergic systems are highly conserved across the species
studied here, which have a long history of separate evo-
lution (Jarvis et al. 2005). This could result from a common
selection pressure for a structure that serves executive
functions, i.e., the control of higher order processes. This
includes the integration and manipulation of information
from all modalities in order to generate a proper behavior
in a given situation. These functions rely on specific con-
nections to other brain structures and the modulation of
information flow through these circuits. Thus, similar
evolutionary pressures on information processing in birds
might result in a comparable or analogue pattern of specific
receptor compositions that would resemble those in the
neocortex of mammals. Future studies need to examine
differences between various bird species, as well as
between different mammalian species to confirm these
conclusions.
Acknowledgments Supported by a grant from the BMBF through
the Bernstein Focus Group ‘‘Varying Tunes’’ to O.G.
Conflict of interest The authors declare that they have no conflict
of interest.
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