Do rats have a prefrontal cortex?

Abstract

The lack of a single anatomical or functional definition of 'prefrontal cortex' has led to different and, in some respects, controversial views on the existence of a prefrontal cortex in non-primate mammals, in particular in rats. Until the classic paper by Rose and Woolsey [Res. Publ. Assoc. Nerv. Ment. Dis. 27 (1948) 210], the general idea was that a prefrontal cortex is unique to primate species. Rose and Woolsey's 'prefrontal cortex' definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsal thalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomical and functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about the nature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functional characteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortex that includes not only features of the medial and orbital areas in primates, but also some features of the primate dorsolateral prefrontal cortex.

Full text

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Behavioural Brain Research 146 (2003) 3–17
Review
Do rats have a prefrontal cortex?
Harry B.M. Uylingsa,b,∗, Henk J. Groenewegenb, Bryan Kolbc
aNetherlands Institute for Brain Research, KNAW, Graduate School Neurosciences, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
bDepartment of Anatomy, Graduate School Neurosciences, VU University Medical Center, Amsterdam, The Netherlands
cCanadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada T1K 3M4
Abstract
The lack of a single anatomical or functional definition of ‘prefrontal cortex’ has led to different and, in some respects, controversial
views on the existence of a prefrontal cortex in non-primate mammals, in particular in rats. Until the classic paper by Rose and Woolsey
[Res. Publ. Assoc. Nerv. Ment. Dis. 27 (1948) 210], the general idea was that a prefrontal cortex is unique to primate species. Rose and
Woolsey’s ‘prefrontal cortex’ definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsal
thalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomical
and functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about the
nature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functional
characteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortex
thatincludesnotonlyfeaturesofthemedialandorbitalareasinprimates,butalsosomefeaturesoftheprimatedorsolateralprefrontalcortex.
© 2003 Elsevier B.V. All rights reserved.
Keywords: Prefrontal cortex; Rat; Primates; Parallel circuits; Basal ganglia; Mesocortical dopaminergic system; Monoamines; Acetylcholine
Abbreviations: ac, anterior commissure; ACd, dorsal anterior cingulate
area; ACv, ventral anterior cingulate area; AId, dorsal agranular insular
area; AIp, posterior agranular insular area; AIv, ventral agranular insu-
lar area; AM, anterior medial thalamic nucleus; AO, anterior olfactory
nucleus; BAC, basal amygdaloid complex; cc, corpus callosum; CPm,
caudate–putamen complex, medial part; DStr, dorsal striatum; Ent, en-
torhinal area; FL, forelimb area, according to Zilles [157]; Fr1/3, frontal
cortical areas 1 and 3, according to Zilles [157]; Fr2, frontal cortical area
2, rostral to about −1mm from bregma; GPe, globus pallidus, external
segment; GPi, globus pallidus, internal segment; Hip, hippocampus; HL,
hindlimb area, according to Zilles [157]; IL, infralimbic cortical area;
IMD, intermediodorsal thalamic nucleus; LO, lateral orbital cortical area;
MC, motor cortex; MDl, mediodorsal thalamic nucleus, lateral segment,
includes here MDpl; MDm, mediodorsal thalamic nucleus, medial seg-
ment; MDm(a), anterior part of MDm; MDm(p), posterior part of MDm;
MDpl, mediodorsal thalamic nucleus, paralamellar segment; MO, medial
orbital cortical area; OB, olfactory bulb; Oc1, primary occipital (visual)
cortex [157]; Oc2L, lateral part of occipital cortex, area 2 [157]; Oc2M,
medial part of occipital cortex area 2 [157]; Par1(dysgr), dysgranular part
of parietal cortex area 1 [157]; Par2, parietal cortex area 2 (supplemen-
tary somatosensory cortex) [157]; PC, posterior cingulate area; PC/CL,
paracentral and central lateral thalamic nuclei; PF, parafascicular thala-
mic nucleus; Pir, (pre)piriform cortex; PL, prelimbic cortical area; PRh,
perirhinal cortical area; PV, paraventricular thalamic nucleus; rs, rhinal
sulcus; RSA, agranular retrosplenial cortex; RSG, granular retrosplenial
cortex; SMA, supplementary motor area; SNc, substantia nigra pars com-
pacta; SNr, substantia nigra pars reticulata; SNrdm, dorsomedial part of
SNr; STh, subthalamic nucleus; Te2, area 2 of temporal cortex [157]; TT,
1. Introduction
The volume of the cerebral cortex of a rat is about a
hundred times smaller than that of the cerebral cortex of
macaques, and about a thousand times smaller than that
of humans [138]. This increase in cortical volume in pri-
mates is paralleled by an evolutionary differentiation of
cortical areas and by the development of more complex,
cognitive cerebral functions [114]. In this light it is not
surprising that discussions are ongoing about whether or
not particular cortical areas in the rat brain are comparable
with specific cortical areas in primates. Recently this issue
has been raised about the prefrontal cortex, in particular
whether or not rats possess a prefrontal region that is com-
parable with the dorsolateral prefrontal cortex in primates
[111,114]. Such a question is complicated, since the rat
cortical fields are generally less evoluted, less differenti-
ated and less segregated than those in the primate cerebral
cortex. The primate prefrontal cortex consists of various
taenia tecta; VA, ventral anterior thalamic nucleus; VL, ventral lateral
thalamic nucleus; VLO, ventrolateral orbital cortical area; VM, ventral
medial thalamic nucleus; VMm, medial part of VM; VO, ventral orbital
cortical area; VP, ventral pallidum; VStr, ventral striatum
∗Corresponding author. Tel.: +31-20-5665500; fax: +31-20-6961006.
E-mail address: h.uylings@nih.knaw.nl (H.B.M. Uylings).
0166-4328/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2003.09.028

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H.B.M. Uylings et al./Behavioural Brain Research 146 (2003) 3–17
anatomically different subfields [10,23,138], roughly di-
vided in a dorsolateral, a medial and an orbital region [44].
These different subdivisions of the primate prefrontal cor-
tex are thought to be involved in different cognitive and
emotion functions [8,12,31,44,99]. It is generally accepted
that the prefrontal cortex is involved in different aspects
of executive control and that the neuronal basis for these
functions is formed by the extensive neuronal networks in
which the prefrontal cortex is intricately involved. Although
Preuss [111] did not question the existence of a rat pre-
frontal cortex in general, this was the way it was perceived
by many primate researchers. However, Preuss [111] and
Preuss and Kaas [114] questioned explicitly the existence of
an equivalent of the primate dorsolateral prefrontal cortex
in non-primate species. To answer the question whether rats
have a dorsolateral-like prefrontal cortex we must consider
various anatomical and functional criteria that define the
different prefrontal regions. On the basis of the structural
and functional data reviewed below, we conclude that rats
have a prefrontal cortex, part of which (in particular the dor-
somedial shoulder region) displays features that resemble
characteristics of the primate dorsolateral prefrontal cortex.
2. Criteria for the definition of a prefrontal cortex
For a long time after Brodmann’s studies [17] the pre-
frontal cortex was considered unique to the primate species
and called the ‘frontal granular cortex’ [14]. The definition
of prefrontal cortex at that time was based upon the cy-
toarchitectonic criterion of having a granular layer IV and
a location rostral to the agranular (pre)motor areas. How-
ever, comparing different cortical areas in more distantly re-
lated species solely on the basis of cytoarchitectonic criteria
appeared to be untenable. For example, the primary motor
cortex in rats is considered to be homologous to the one in
monkeys [105], but this cortical area is agranular in mature
primates and granular in rats. Likewise, Barbas and Pandya
[10] consider limbic cortices in primate brains, which are
agranular and dysgranular (i.e. layer IV is not and is not eas-
ily discernible, respectively) as part of the prefrontal cortex.
These are just two examples to emphasize why cytoarchitec-
tonic criteria have been replaced by other criteria in seeking
homologies between different brain areas in more distantly
related species. It is now generally accepted that the follow-
ing criteria have to be taken into account when discussing
homologies between cortical areas in different species: (1)
the pattern of specific connections and the relative density
of these connections; (2) the functional (i.e. electrophys-
iological and behavioral) properties; (3) the presence and
specific distribution of different neuroactive substances and
neurotransmitter receptors; (4) the embryological develop-
ment; and (5) only for closely related species, the cytoarchi-
tectonic characteristics. The greater the similarities between
the characteristics, the more likely it is that brain regions
are homologous. In the following account we will employ
the first three criteria for comparing prefrontal cortical areas
in primates and rats. These three criteria also were applied
by Preuss [111]. From this perspective we will consider the
connections of the rat and primate prefrontal cortices with
thalamic, basal ganglia, cortical, limbic and monoaminergic
structures, with respect to both pattern and density. Subse-
quently, we will review comparatively the functional prop-
erties of prefrontal areas in rats and primates.
3. Neuronal networks involving the prefrontal cortex
3.1. Connections between prefrontal cortex and thalamus
Thalamocortical connections are important for cortical
differentiation and specialization (e.g. [90]). The reciprocal
connections of the major thalamic nuclei are therefore used
to define cerebral cortical areas. At the time of Rose and
Woolsey [126], the mediodorsal nucleus of the thalamus
was assumed to be the only nucleus with thalamocorti-
cal projections to the prefrontal cortex, and was therefore
viewed as the ‘defining’ nucleus. However, with the ad-
vent of more refined anterograde and retrograde tracing
techniques, it became apparent that the (prefrontal) cor-
tical areas that receive mediodorsal thalamic input also
are connected with other thalamic nuclei. Thalamic nuclei
other than the mediodorsal nucleus that reach the prefrontal
cortex include the intralaminar and midline nuclei, the
anterior medial nucleus and the rostral parts of the ven-
tral complex [11,12,15,35,50,55,56,67,72,133]. In addition,
thalamic mediodorsal nucleus projections appear to reach
some cortical areas outside the prefrontal cortex, such as
the premotor, motor, temporal and parietal cortices, as has
been demonstrated in, for example, macaque monkeys, cats,
sheep, and dogs [1,37,50,56,72,100,136]. Among others,
Nauta [103] and Leonard [88] regarded the reciprocity of
the cortical projections of the thalamic mediodorsal nu-
cleus as an important criterion for defining the prefrontal
cortex. However, this definition also does not lead to an un-
ambiguous delineation of the prefrontal cortex. Therefore,
Uylings and Van Eden [138] suggested inclusion of only
those cortical areas in the prefrontal cortex for which the
reciprocal connections with the mediodorsal nucleus (MD)
are stronger (i.e. in terms of a higher number of projecting
neurons and a higher density of terminals) than the recip-
rocal connections with other thalamic nuclei. This feature,
together with the pattern of cortico-cortical connections, has
led us to include the primate and rat anterior cingulate cor-
tex in the prefrontal cortex [138]. This approach in defining
the prefrontal cortex is strengthened by the recent analysis
of Kötter, who demonstrated the special, predominant posi-
tion of the mediodorsal nucleus for the macaque prefrontal
cortex on basis of multidimensional scaling analysis of
the thalamoprefrontal cortical projections (Kötter, personal
communication, 2003). In addition, Barbas et al. [11], Der-
mon and Barbas [35] and Ray and Price [122] showed in

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Fig. 1. The extent of rat’s prefrontal cortex. (A, B). The increase in what is considered to be prefrontal cortex due to improvements in anatomical
techniques. Fine dots indicate the area described by Leonard [88], large dots the extension described by Krettek and Price [87], oblique lines the extension
proposed by Groenewegen [54] and vertical lines the extension proposed by Verwer in [138]. The nomenclature of Krettek and Price has been followed
with the exception of the neutral term frontal area 2 (Fr2), see Section 6 in text. MO and VO are the medial and ventral orbital areas and AI the rat
anterior insular area. (C) The view illustrated by Preuss and Kaas [114], modified from Preuss [111], in which ACd is now incorporated in the anterior
cingulate cortex. In the view of Preuss and Kaas shown in (C) the anterior cingulate (AC), the prelimbic (PL) and the infralimbic (IL) areas of (A) form
the prefrontal cortex, while the orbital and lateral prefrontal cortex are conspicuously lacking. For abbreviations see the Abbreviations section.
rhesus monkey that the majority of the thalamic neurons
projecting to the prefrontal cortex, as it has been defined be-
fore, are located in the mediodorsal nucleus. This also goes
for the rat prefrontal cortex (see Fig. 1) [54,87,123,140].
Dermon and Barbas [35] reported that area 25 in
macaques (which is considered to be a prefrontal corti-
cal area, e.g. [10,106]) receives more thalamic afferents
from the thalamic ventral anterior nucleus than from
the mediodorsal nucleus. When this is also true for the
efferent corticothalamic projections from area 25, then
macaque area 25 should probably not be included in the
prefrontal cortex [12]. A similar situation holds likely
for the ventrolateral orbital cortical area (VLO) in the rat
[54,123,155].

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H.B.M. Uylings et al./Behavioural Brain Research 146 (2003) 3–17
For a further comparison of monkey and rat thalamic data
it is important to know that in non-human primates thalamic
ventral nuclei have a differential cortical projection pattern
for the prefrontal, premotor and motor cortex, respectively
[66]. The thalamic ventral anterior (VA) and posterior ven-
tromedial (VMp) nuclei project quite diffusely and spread
out over an extensive region of neocortex (i.e. premotor, sup-
plementary motor area (SMA), supplementary eye field, an-
terior cingulate (AC) and posterior parietal cortex), but these
projections have a relatively higher concentration in the pre-
frontal cortex. In contrast, the anterior ventrolateral (VLa)
cortical projections are more concise and concentrated in
premotor and SMA areas, with additional lesser projections
also to the motor area. In addition, the posterior ventrolat-
eral nucleus (VLp) is the principal source of projections to
primary motor area 4, but projects also to premotor, SMA,
and some to posterior parietal cortex [66]. In rats the topog-
raphy and the pattern of connectivity of the mediodorsal nu-
cleus is rather comparable with the one in monkeys [54,56].
The VA in rats, however, is usually included in the VL due
to its difficult cytoarchitectonic delineation [56,65,138].
In the last decade the inclusion of the rat frontal area
2 (Fr2) and the dorsal anterior cingulate area (ACd) (see
Fig. 1) in the prefrontal cortex has been disputed by Preuss
[111] and Condé et al. [28,29]. The results of Condé et al.’s
retrograde tracer studies on thalamic afferents [28] and
cortico-cortical afferents [29] to rat medial frontal cortex
were decisive for their and Preuss’ thesis, namely that the
rat Fr2 (also called the precentral medial area (PrCm) or
agranular medial cortex (Agm), see below) and the rat ACd
are premotor areas and do not belong to the prefrontal
cortex. As a consequence they denied the presence of
dorsolateral-like prefrontal cortical features in rats. Condé
et al. [28] described in their retrograde tracer study that
only a few neurons from the mediodorsal thalamic nucleus
project to Fr2 and ACd and that a higher number of thalamic
projecting neurons are positioned in the intralaminar, the
ventrolateral (VL) and ventromedial (VM) nuclei. In this
respect, their Fig. 12 [28] is conspicuous for illustrating a
case with a relatively high number of MD neurons project-
ing to ACd. Furthermore, several groups [54,87,121] have
observed in extensive anterograde and retrograde tracing
studies that the rat Fr2 and ACd (Fig. 1) have a very dense
reciprocal connection with the paralamellar or ventrolateral
segment of the thalamic mediodorsal nucleus. This can also
be concluded from the anterograde and retrograde tracer
studies of Reep and Corwin [124], which were directed
especially to the Fr2 (their AGm). Reep and Corwin dis-
tinguished caudal AGm from mid and rostral AGm, and
showed that rostral and mid AGm receives thalamic affer-
ents from a higher number of neurons in the mediodorsal
nucleus. It appeared that only the caudal AGm has afferents
from cells mainly located in VL and only a few neurons in
the mediodorsal nucleus. However, this part of AGm or Fr2
[156] is not included in the rat prefrontal cortex as defined
by Krettek and Price [87], Groenewegen [54], Uylings and
Van Eden [138], and Van Eden et al. [142], because it is
caudal to about −1mm from bregma (see also note below).
In addition, Vertes [143] showed that both ACd and Fr2
have strong projections particularly to the MD. Therefore,
we conclude that ACd and Fr2 have a more prefrontal than
premotor type of thalamic connections. On basis of both
thalamic and subcortical and cortical connections we sup-
pose also that the caudal Fr2 and (supragenual) parts of ACd
incorporates a zone homologous to the macaque frontal eye
field (FEF) [138,142]. This is corroborated by electrophys-
iological studies [59,104] and by unilateral lesion studies
causing multimodal neglect [73,95].
We realize the pitfalls of the quantitative definition of our
anatomical ‘prefrontal cortex’ definition. Even with the use
of modern neuroanatomical tracing techniques, it is rather
difficult to determine unequivocally for those cortical re-
gions showing considerable overlap of connections from
various thalamic nuclei, which of these thalamic nuclei pro-
vides the strongest connections. For example, comparison
of numbers [139] of different types of neurons projecting to
a particular cortical area with retrograde tracing implies the
assumption that the extent of these axonal terminal fields is
similar in the different regions that have been injected with
a particular tracer. This is not always the case, however. It
is therefore important to consider in addition the quality of
connections (e.g. ‘driver’ and ‘modulator’ type of thalamic
connections [56,132]), the cortico-cortical and subcortical
neuronal networks and functional properties in which dif-
ferent prefrontal cortical areas have a particular, different
position.
3.2. Prefrontal cortex–basal ganglia relationships
The frontal lobe as a whole has a special relationship
with the basal ganglia in that it is the part of the cerebral
cortex that receives the main input from the basal ganglia,
through a relay in the thalamus [97]. This basal ganglia
influence has long been known for the motor and premotor
cortices, but the frontal areas anterior to the (pre)motor
cortices (i.e. mostly the prefrontal cortical areas) are not
excepted from this particular subcortical influence. Like the
frontal cortex, the parietal, occipital and temporal cortices
all project to the basal ganglia, in particular the striatum, but
these posteriorly located cortices do not receive information
back from the basal ganglia, with the exception of area TE
in the inferotemporal cortex [96]. A particular subset of
thalamic nuclei (i.e. the mediodorsal, ventromedial, ventral
anterior and, to a lesser degree, the ventral lateral nuclei)
form the essential link between the pallidum and substantia
nigra pars reticulata, as the output structures of the basal
ganglia [2,58,94,98] and the (pre)frontal cortex. It is also
relevant to emphasize the high degree of topographical or-
ganization in the frontal cortical–basal ganglia connections
and in the basal ganglia–thalamic projections. This topo-
graphical organization forms the basis for the existence of
a number of parallel, largely functionally segregated basal

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Fig. 2. Schematic diagrams to illustrate, for the rat brain, the involvement of different parts of the (pre)frontal cortex in various basal ganglia–thalamocortical
circuits and amygdaloid and midline/intralaminar thalamic circuits. Four basal ganglia–thalamocortical circuits are depicted with similar organizational
characteristics. Compare also the organization of similar circuits in primates [2]. All four circuits involve different parts of the (pre)frontal cortex, the dorsal
or ventral striatum, the pallidal and nigral complex and the ventral and medial thalamic nuclei. The present diagram emphasizes the ‘closed’ character
of these circuits, but they may in various specific ways be interconnected, and the (pre)frontal cortical and basal ganglia way stations have extensive
projections outside the depicted circuits. (A) ‘Motor circuit’: note the projections from the parafascicular thalamic nucleus to the motor cortex and the
dorsal striatum, together with the absence of the amygdala connections. (B) ‘Dorsal shoulder prefrontal’ circuit (Fr2 and ACd): the cortical and striatal way
stations of this circuit receive specific projections from the intralaminar thalamic complex (PC/CL) and the anterior part of the basal amygdaloid complex.
(C) ‘Medial prefrontal/anterior cingulate’ circuit (PL/IL/MO/ACv): the paraventricular thalamic nucleus and the posterior part of the basal amygdaloid
complex are strongly involved in this particular circuit. (D) ‘Lateral prefrontal/agranular insular’ circuit (AIv/AId): the intermediodorsal thalamic nucleus
and the anterior part of the basal amygdaloid complex project to the cortical and striatal way stations of this circuit. For a comparison with the circuits
described in primates, it is important to note that the topography of subcortical afferents and thalamocortical efferents of the thalamic mediodorsal nucleus
in rats and primates is largely similar [56]. The medial (and central) segments of the rat mediodorsal nucleus resemble the magnocellular part of the
primate MD. The lateral (and paralamellar) segments of the rat MD are comparable with the multiform and densocellular parts of the primate MD.
ganglia–thalamocortical circuits that have been identified
both in primates [2,3,58,98]. Alexander et al. [2,3] identi-
fied five circuits in primates: a ‘motor’, an ‘oculomotor’,
an ‘anterior cingulate/medial orbitofrontal’, a ‘lateral
orbitofrontal’, and a ‘dorsolateral’ prefrontal circuit, which
are further subdivided by Middleton and Strick [98]. In rats,
similar circuits have been described, as illustrated in Fig. 2.
Further important aspects of the circuitry in which the
prefrontal cortex and the basal ganglia are involved concern
the specific relationships of the projections from the mid-
line/intralaminar thalamic complex as well as the amygdala
and, to a lesser extent the hippocampus, to the cortical and
striatal relay stations in the basal ganglia–thalamocortical
circuits (Fig. 2) [9,55,57,58,93,144]. In both rats and pri-
mates, the circuits that involve the prefrontal cortical areas
are characterized by amygdaloid inputs. However, in rats
the dorsal anterior cingulate (ACd) and Fr2 areas receive the
least amygdaloid fibers of the prefrontal areas [57], while
also in nonhuman primates the dorsolateral prefrontal cortex
has the weakest amygdaloid input in the prefrontal cor-
tex [5]. All these connectional aspects point to similarities
between prefrontal cortex–basal ganglia–thalamocortical
circuits of primates and rats. In particular, they show a num-
ber of comparable features for both the primate dorsolateral
prefrontal cortex and the rat ACd and Fr2 areas.
3.3. Cortico-cortical networks
Both the thalamocortical and the cortico-cortical con-
nections with the rat and primate prefrontal cortex are
predominantly ipsilateral [1,54,108,142]. The majority of
terminal axons in the prefrontal cortex are cortical afferents

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H.B.M. Uylings et al./Behavioural Brain Research 146 (2003) 3–17
[108,142]. In both rats and primates the prefrontal cortex is
extensively connected with different cortical areas such as
premotor, somatosensory, auditory, visual, olfactory, gus-
tatory and limbic cortical areas [7,24,26,142]. Pandya and
Yeterian [108] showed that in macaques the connections
between the prefrontal and other cortical areas are recipro-
cal and that such connections exist preferentially between
cortical areas with a similar level of cytoarchitectonic differ-
entiation. However, connections between distinct prefrontal
cortical areas exist both between areas with similar levels
of cytoarchitectonic differentiation as well as between areas
with different levels of differentiation. In addition, Barbas
etal.[12]showedthatthecytoarchitectonicallylessdifferen-
tiated prefrontal regions have fewer specific cortico-cortical
connections. They receive projections from two or more
cortical areas representing different sensory modalities to-
gether with a substantial input from limbic cortices. The
cytoarchitectonically more highly differentiated (thus eu-
laminate or strongly granular) prefrontal areas receive more
specific projections representing only one or two different
modalities, and relatively few projections from limbic cor-
tices. In primates, in particular the macaque, the dorsolateral
prefrontal cortex has extensive cortico-cortical connections.
The rat data currently available do not contradict this
“hierarchical” theory of Pandya and Barbas, but more in-
formation is required before definitive conclusions can be
drawn. As mentioned above the retrograde tracer study on
cortico-cortical afferents of Condé et al. [29] has strength-
ened the view of Condé et al. and Preuss [111] that the rat
Fr2 and ACd is largely a premotor cortex and do not belong
to the prefrontal cortex. By excluding this ‘dorsal shoulder’
region from the rat prefrontal cortex, they arrived to their
opinion, that the prefrontal cortex in rats lack features of the
primate dorsolateral prefrontal cortex [29,111]. Condé et al.
[29] concluded that Fr2 and ACd have the main features
of a premotor cortex and “none of the features of any area
of the macaque prefrontal cortex”. A typical feature of the
macaque prefrontal cortical areas is, as noted above, how-
ever, the property of a multimodal association area in a hi-
erarchical organized cortex [108] and the feature of a nodal
station in several distributed parallel networks [26,52,113].
Like the macaque prefrontal cortex, the rat prefrontal cortex
receives multimodal cortico-cortical projections from motor,
somatosensory, visual, auditory, gustatory, and limbic cor-
tices in such a way that the rat prefrontal cortex appears to be
a nodal station embedded in several parallel networks [142].
Moreover, Van Eden et al. [142] have shown (with antero-
grade labeling) that Fr2 and ACd receive more projections
from somatosensory and associational visual cortices than
from the primary motor cortex. The macaque prefrontal cor-
tex has the strongest connections with posterior parietal and
temporal association areas [26,27]. Rat equivalents are not
well described for these parietal and temporal association
areas [142], which makes a good comparison not yet possi-
ble. The data available indicate extensive, reciprocal connec-
tions with premotor, motor, somatosensory, visual, auditory
and paralimbic cortical regions (see Fig. 3). The reciprocal
cortico-cortical connections reveal at least three subfields in
the rat medial prefrontal cortex, i.e. a ‘dorsal shoulder’ re-
gion (Fr2 and ACd); a rostral part of the medial prefrontal
cortex; and the prelimbic and infralimbic cortices.
The architectonically less differentiated areas in the rat,
the infralimbic and prelimbic cortices and the lateral pre-
frontal cortex (i.e. agranular insular cortices), have recip-
rocal connections with the perirhinal and entorhinal cortex,
and with the CA1 field and subiculum of the hippocampal
formation [57,62,145]. The rostral part of the rat medial pre-
frontal cortex has reciprocal connections with motor, mixed
somatosensory-motor, and somatosensory association cor-
tices. Thus, premotor characteristics appear to coincide here
with prefrontal characteristics [138]. The ‘dorsal shoulder’
region has reciprocal connections mainly with visual cor-
tices and the retrosplenial cortex. As mentioned above the
caudal part of the dorsal shoulder region appears to incor-
porate features of the frontal eye field.
It is of interest to note that Fuster [44,45] views the in-
teractions of prefrontal with other cortices in the context
of ‘perception–action cycle’. This is a hierarchical concept
too. The prefrontal cortex and other cortices are functionally
connected for as long as the behavior contains novelty, un-
certainty or ambiguity, and has to span time intervals with
short-term or working memory. These functional connec-
tions disappear or weaken when the action becomes auto-
matic. The action is then integrated in lower brain structures
[45].
3.4. The prefrontal gating position in cholinergic and
monoaminergic systems
Data on the cholinergic and monoaminergic transmitter
systemstogetherwithprefrontalcortico-corticalconnections
in primates and rats also show the unique gating position of
the prefrontal cortex.
In both rats and primates the entire neocortex receives
cholinergic innervation from the basal forebrain nuclei. The
prefrontal cortex, in addition, gets cholinergic fibers from
the laterodorsal tegmental nucleus. Likewise in both species,
the prefrontal cortex (in primates mainly the orbital and
medial PFC and in rats mainly the medial PFC) is the only
cortical region that has direct projections back to these basal
forebrain and brainstem nuclei [48,49,57,127,138,156].
The noradrenergic fibers from the locus coeruleus and the
serotonergic fibers from the dorsal and median raphe nuclei
are widely distributed over almost the entire neocortex. Also
with respect to these transmitter systems in both rats and
primates certain prefrontal areas are the only cortical areas
that project back to the locus coeruleus and to the dorsal and
median raphe nuclei. In primates the cortical projections to
the noradrenergic locus coeruleus and the serotonergic raphe
nuclei derive from the dorsolateral PFC [6]. In rats the corti-
cal projections to the locus coeruleus derive from the medial
PFC and the agranular insular PFC areas, while the cortical

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9
Fig. 3. A diagram of cortico-cortical connections of the rat prefrontal cortex (modified from [138]). For abbreviations see the Abbreviations section.
projections to the dorsal and median raphe nuclei are from
the medial PFC, especially its ventral part [60,63,64,138].
In rats, the cortical terminal fields of dopaminergic fibers
are mainly restricted to the prefrontal areas and the entorhi-
nal cortex, whereas only the prefrontal cortex (both medial
and agranular insular PFC) projects back to the dopamin-
ergic neurons in ventral tegmental area (VTA or A10) [25]
and the dopaminergic pars compacta of the substantia ni-
gra (A9). The rat prefrontal cortex receives distinct paral-
lel dopaminergic inputs. The supragenual anterior cingulate
cortex receives dopaminergic fibers in the superficial layers
from the pars compacta of the substantia nigra and in the
deeper layers from the lateral part of the ventral tegmen-
tal area [89,91]. The ventral tegmental area is the origin
of the major dopaminergic input in the rat prefrontal cor-
tex and different parts of the ventral tegmental area appear
to project to different prefrontal areas [69]. Particularly in
primates, cortical dopaminergic fibers appear not to be re-
stricted to the prefrontal cortex. As suggested [47,138] this
appears to be caused mainly by extension of dopaminergic
midbrain cellular groups such as the retrorubral areas A8
and A9 [152]. Direct recurrent projections from the primate
dorsolateral prefrontal cortex to the medial substantia nigra
pars compacta (A9) have been reported [89], but they can
also be expected to project to the ventral tegmental area on
the basis of the above.
In rats the histaminergic neurons in the tuberomammillary
hypothalamic region have reciprocal connections with ven-
tromedial prefrontal cortex [154]. These connections have
not yet been described for primates.
4. Functional characteristics of prefrontal areas
The function of any brain region is to produce behavior.
Thus, a key issue in identifying similarities in cortical areas
across species must be function. One of the major obsta-
cles in comparing the behavior of different species of mam-
mals is that each species has a unique behavioral repertoire
that permits the animal to survive in its particular environ-
mental niche. There is therefore the danger that neocortical
organization is uniquely patterned in different species in a
way that reflects the unique behavioral adaptation of differ-
ent species. One way to address this problem is to recognize
that although the details of behavior may differ somewhat,
mammals share many behavioral traits and capacities (e.g.
[81]). For example, all mammals must detect and interpret
sensory stimuli, relate this information to past experience,
and act appropriately. Similarly, all mammals appear to be
capable of learning complex tasks under various schedules
of reinforcement (e.g. [146]). The details and complexity of
these behaviors clearly vary, but the general capacities are
common to all mammals. Warren and Kolb [146] proposed
that behaviors and behavioral capacities demonstrable in
all mammals could be designated as class-common behav-
iors. In contrast, behaviors that are unique to a species and
that have presumably been selected to promote survival in a
particular niche are designated as species-typical behaviors.
This distinction is important because it has implications for
the organization of the cerebral cortex.
Kaas [68] has argued, for example, that all mammalian
species have similar regions devoted to the analysis of ba-
sic sensory information (e.g. primary visual (V1), primary
auditory (A1), and primary somatosensory (S1) areas), the
control of movement (primary motor, M1), and a frontal re-
gion involved in the integration of sensory and motor infor-
mation. We can extend Kaas’s idea by suggesting that these
regions have class-common functions. To be sure, there are
large species differences in the details of the class-common
behaviors. Monkeys (and humans) have chromatic vision
compared to the largely achromatic vision of cats or rats.
Nevertheless, in all mammalian species studied, removal of

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H.B.M. Uylings et al./Behavioural Brain Research 146 (2003) 3–17
visual cortex severely disrupts object recognition. Indeed,
although the visual cortex of the rat has often been portrayed
as primitive in organization, the visual acuity of rats is sur-
prisingly good and the tuning characteristics of visual neu-
rons is strikingly similar to that of larger-brained mammals.
Similarly, rats and cats have a large somatosensory represen-
tation of the whiskers, whereas monkeys and humans have
no such representation but in all species the somatosensory
cortex functions to represent skin-related receptors for tac-
tile sensations. Thus, both the visual and tactile recognition
of objects are class-common functions, even though the de-
tails of this recognition may vary in a species-typical man-
ner. A similar argument can be made for motor functions
[147]. Intracortical stimulation studies have shown that all
mammals have a motor map (e.g. [153]) in which the relative
motor facility of different body regions is reflected by the
size of the motor representation. Curiously, although there
are clear interspecies differences in the capacity to use the
forelimbs for object manipulation [61], it has become appar-
ent from the work of Whishaw et al. [148,149] that the ca-
pacity for independent digit manipulation, and the cerebral
organization of this control, is strikingly similar between
rodents and primates. Indeed, recent taxonomic studies of
mammalian evolution have noted that rodents and primates
are more closely related than had been realized previously.
For example, they are more related than cats and primates
are [112,138]. This similarity is especially germane to com-
parisons of frontal lobe function between primates and ro-
dents, given that one primary function of the frontal lobe is
to control the initiation and organization of movement.
As we look for general class-common functions of the
frontal cortex we might anticipate that if the frontal cortex
of mammals developed because all mammals face common
functional problems related to the organization of behav-
ior, then we should be able to identify these functions. One
place to begin searching for class-common frontal functions
is to consider what animals use sensory inputs for. The most
obvious function is to guide behavior on line, such as in
the visuomotor control of movements in space or the iden-
tification of food items using visual, tactile, and olfactory
information. But the sensory world has far more informa-
tion available than the brain can handle at one time so there
must be some system to select information as well as to
focus and maintain attention. Similarly, although behavior
can be directed to sensory stimuli on-line, it can also be
related to information that is stored or expected. Stored in-
formation may be in a type of scratch-pad memory system,
which is often referred to as working memory and implies
a short-term erasable storage of information, or by a type of
long-term memory system in which information is stored for
an extended time. In both instances the stored information
is used to select and generate behavior that is appropriate
for the particular context. The behaviors that are generated
may be novel, and directly related to the sensory events, or
they may be preprogrammed in chains that are innate but
still must be selected with respect either to ongoing sensory
information or to internal states. Thus, there must be some
type of master (sometimes referred to as executive) control
system that selects behavior. It is our contention that the
class-common function of the prefrontal cortex is to select
and generate behavior patterns. In addition, it is proposed
that this system has a working memory subsystem but that
it uses a long-term memory store that is largely a func-
tion of the medial temporal regions. Although this general
view of prefrontal functioning is hardly novel (see reviews
[44,52,78,109]), it is the idea that a prefrontal system with
such functions will be found in all mammals that is the key
concept in the current discussion.
One prediction from our general hypothesis is that all
mammals with damage to the prefrontal homologue should
show functional disruptions of the same general sort. The
prefrontal cortex is extensive in most mammals, however, so
we might also anticipate that there will be some subdivision
of functions across the prefrontal regions in different species
[138]. The organization of the subdivisions is likely to have
some species-typical characteristics, however. Consider, for
example, the relative importance of vision to the control of
forelimb movement in primates versus a parallel olfactory
control of forelimb movement in the rat (e.g. [148]). Such
differences would be expected to be reflected in differences
in the subtle organization of the prefrontal subregions. We
shall review first the evidence for general symptoms of
prefrontal injury in the major subdivisions of primates and
rodents, and then consider the issue of how to compare
functions of the prefrontal subregions across the two orders.
4.1. Effects of frontal lesions in primates
As noted earlier, it is possible to distinguish function-
ally three distinctly different frontal lobe regions in humans.
Thus, in addition to the motor and oculomotor areas, there
are the dorsolateral frontal region, the lateral orbitofrontal
region, and an anterior cingulate/medial orbitofrontal region.
Damage to the dorsolateral frontal region is characterized
especially by deficits in working memory, particularly as it
relates to certain executive processes such as the monitor-
ing and planning of behaviors (e.g. [44,129]). Damage to
the orbitofrontal frontal region is characterized by altered
socio-emotional behaviors, hyperkinesis, deficits in the pro-
cessing of olfactory and gustatory information, and in spon-
taneity (e.g. [22,83,84]). Damage to the anterior cingulate
region is not as well characterized, but can include reduced
response to pain, akinetic mutism, and impaired motor ini-
tiation (e.g. [36]). In addition, all three areas probably pro-
duce some form of attentional deficit but distinctions in the
attentional domain remain unclear and are likely related to
the type of sensory information being processed. Thus, at-
tentional processes related to olfactory and gustatory inputs
are likely related to orbitofrontal regions, those related to
visual inputs are likely related to dorsolateral regions, and
those related to internal states (such as pain) are related to
anterior cingulate regions.

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11
In monkeys the symptoms of lesions to the dorsolateral
prefrontal, orbitofrontal, and anterior cingulate regions re-
spectively produce analogous behavioral deficits to those
observed in humans. In particular, dorsolateral lesions espe-
cially produce deficits in working memory, whereas lesions
that include the frontal eye fields (area 8) produce attentional
deficits (e.g. [44]). Orbitofrontal lesions produce a disinhi-
bition of motor behaviors, abnormalities in social-affective
behaviors, deficits in certain types of olfactory and gusta-
tory processing, and in the association between reward and
external cues (e.g. [125]). Cingulate lesions lead to deficits
in the encoding of movements (including eye movements),
and reduced response to pain. Although an early study
suggested that cingulate lesions produce deficits in delayed
alternation, this is only seen in acquisition and not in reten-
tion, which is rather different than the effect of dorsolateral
lesions (e.g. [115]).
4.2. Effects of frontal lesions in rats
It was demonstrated in the early 1970s that lesions to the
medial and lateral orbital regions in rats produced very dif-
ferent behavioral syndromes, and that these changes were
strikingly similar to those observed in primates with lesions
to the dorsolateral and orbitofrontal regions, respectively
(Table 1; for reviews see [78,79]). For example, damage to
the medial prefrontal (mPFC) area produces severe deficits
in acquisition and retention of working memory tasks such
as delayed response [86], delayed alternation [38,86,151],
different types of delayed nonmatching-to-sample tasks
(e.g. [19,40,85,107]) and related tasks (e.g. [71,118]). More
Table 1
Summary of the effects of mPFC and OFC lesions in rats
Behavioral impairmentReferences
mPFC
Visual working memory
Strategy formation
Spatial reversal
Habituation
Skilled reaching
Motor sequencing
Attention
Attention set shift
Food hoarding
Fear extinction
Conditioned emotional responses
Operant reversal learning
Conflict behavior
Operant working memory
[86]
[85]
[38,86]
[74,76]
[149]
[80]
[18,102]
[16]
[75]
[116]
[42,43]
[33,41]
[20]
[19]
OFC
Hyperactivity
Social behavior
Incentive association
Odor working memory
Configural odor learning
Odor reversal learning
Feeding
[74]
[32,77]
[46]
[107]
[150]
[128,131]
[75]
recently, deficits have been shown in various types of atten-
tional tasks [102] and in a task requiring a reversal or a shift
of attention from one set of cues to another [16,33,41,82].
Medial frontal lesions also produce disruptions to the pro-
duction of various motor and species-typical behaviors that
require the ordering of motor sequences, such as in nest
building, food hoarding, or latch opening [74,75,80,134].
Although these types of experiments were viewed by
many as convincing evidence of parallel (and perhaps ho-
mologous) functions in rodents and primates, Preuss [111]
remained unconvinced. Indeed, he has argued that in view
of what he believed to be significant anatomical differences,
and the failure to find prolonged or long-lasting deficits after
mPFClesionsinrodentsthatareequivalenttothoseobserved
in primates with dorsolateral lesions, that the research on the
mPFC of the rat has little to offer to those interested in un-
derstanding frontal lobe functioning in primates. Preuss was
wrong on his conclusion that rats with medial frontal do not
have significant memory deficits (e.g. [85,86]), but the fact
that most studies of medial frontal function had made lesions
including all of the medial prefrontal subregions did pro-
vide grist for his skepticism. Accordingly, in the past decade
there has been considerable interest in dissociating the dif-
ferent medial prefrontal subregions in the rat. It has now
become clear that the dorsal anterior cingulate region, and
prelimbic/infralimbic region can be functionally dissociated
[51,60a]. In general, it appears that the PL region is involved
in attentional and response selection functions as well as vi-
sual working memory (e.g. [53]) whereas the more dorsal
regions (ACd) are involved with generating rules associated
with temporal ordering and motor sequencing of behavior
(see reviews [51,70]. Indeed, on the basis of such studies,
Kesner [70] has gone so far as to suggest that the anterior
cingulate region is homologous to Brodmann’s areas 6/46
whereasthePL/ILregionsarehomologouswithBrodmann’s
areas 45 and 47. Additionally, although less is known about
its precise role in behavior, it appears that the IL region
plays a special role in autonomic control, and especially in
the modulation of fear-related behaviors (e.g. [101,116]).
Kesner’s hypothesis will be a difficult one to unequivo-
cally prove or disprove, but it is not necessary for the current
argument, which is simply that the medial frontal regions
have class-common functions that are similar to those of the
dorsolateral and possibly cingulate regions in the monkey
frontal lobe. We suggest that these class-common functions
include functions that are often referred to as executive func-
tions in primates. These functions would include working
memory, the selection of information (often referred to as
attention), and the shifting of attention from one stimulus
attribute to another (e.g. [21]).
There is much more parsimony in reviews comparing the
effects of lateral orbitofrontal lesions in rodents and pri-
mates [130]. The lateral orbital region receives significant
olfactory and taste input and although lateral orbital lesions
do not produce deficits in olfactory or taste discriminations,
they do produce deficits in tasks requiring working memory

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H.B.M. Uylings et al./Behavioural Brain Research 146 (2003) 3–17
for odor or taste information (e.g. [4,34,107,117,120]). Fur-
thermore, lesions to the lateral orbital region disrupt the
learning of cross-modal associations that involve odor or
taste cues (e.g. [150]). More recently, studies by Schoen-
baum and his colleagues (e.g. [46,131]) have emphasized
a role of the orbital cortex in the encoding of the acquired
incentive value of cues. For example, both rats and primates
can show intact performance on discriminations that require
responding to neutral cues (such as a light) that predicts re-
ward, while at the same time showing marked deficits when
the incentive value of the stimulus is reduced. Such deficits
can be seen during extinction when the incentive value of
a stimulus is reduced to zero, yet animals continue to re-
spond to the cue as though reward is expected (e.g. [13,46]).
The role of the orbitofrontal cortex in stimulus-reward as-
sociations is further seen in studies measuring the tuning
characteristics of neurons in the orbital region of both rats
and monkeys [130]. Finally, damage to the orbitofrontal
cortex produces deficits in social and play behavior in rats
(e.g. [32,77]).
The overall pattern of deficits related to orbitofrontal
(OFC) lesions leads to a general conclusion that there is a
class-common function related to making higher order use
of olfactory and taste information. This can be seen easily
in tests that require the association of such information with
events in the world, whether they are learned associations
such as neutral cues and reward or natural stimuli (such as
conspecific odors) or rewards that may be more abstract
(such as social bonding). Although odors obviously play a
reduced role in the control of social behaviors in humans,
the neural networks underlying many social functions re-
mains related to the orbitofrontal cortex.
One region of the rat frontal cortex that has not been
subject to many lesion studies is the more medial and ventral
orbital area (but see [30]). We noted earlier that this region
has ambiguous anatomical characteristics so at present we
must see this region as a somewhat of an enigma.
Taken together, the lesion studies of the prefrontal re-
gions in primates and rodents lead us to conclude that there
is a strong convergence of class-common symptoms across
mammals. Furthermore, it seems likely that most mam-
mals have a gross subdivision of the frontal areas into an
“orbital-like” region involved especially with the control
of socioaffective behaviors, a “dorsolateral-like” area in-
volved especially in working memory, and an “anterior
cingulate-like” area concerned primarily with visceromotor
behaviors and some forms of motor sequencing. To be sure,
there are likely to be significant cross species differences
in details of the anatomical and functional organization of
these areas. The critical point for this paper is that both pri-
mates and rodents, and probably all mammals, have a region
of frontal cortex that can be defined both anatomically and
functionally as prefrontal cortex. Further, it is likely that the
prefrontal cortex is subdivided into at least an “orbital-like”
and another region that may include both “dorsolateral- and
anterior cingulate-like” features. Finally, given the anatomy
reviewed above, it is likely that these latter areas are also
subdivided. If this is so, then it is likely that the primi-
tive mammals that gave rise to extant mammals had a more
or less subdivided prefrontal cortex that evolved to solve
class-common behavioral problems.
5. Conclusions
The present anatomical and functional data indicate that
rats have a prefrontal cortex, in which Fr2 and ACd are in-
corporated. Preuss and Kaas [114] have stated that evidence
available to them at that time “is consistent with the pos-
sibility that the dorsolateral prefrontal cortex is a primate
specialization”. Certainly, the rat prefrontal cortex is not as
differentiated as it is in primates and evolutionary later spe-
cializations are likely, but dorsolateral-like features, includ-
ing both anatomical and functional ones, are shown in rats.
They are present in areas Fr2 and ACd, and functional data
indicate that PL is implicated in some dorsolateral-like fea-
tures.Theseareashavealsofeaturesofothertypeofcortices,
e.g. premotor and anterior cingulate cortex [138]. However,
it holds also for primates that the closer prefrontal cortex
areas are to the premotor cortex the more premotor features
they have.
We focus in this review on rats, but Kosmal’s group from
Warsaw has indicated, that anatomical dorsolateral-like pre-
frontal characteristics are present in dogs as well [92,119,
135,136]. This too would be consistent with the conclusion
that the dorsolateral prefrontal regions of primates are not a
unique specialization.
6. Note on prefrontal nomenclature
A stable and unequivocal nomenclature is desired [110],
although neuroanatomical nomenclature should remain
flexible in order to incorporate new insights [137]. Unfortu-
nately, a generally accepted nomenclature for the prefrontal
cortical areas in rats is still lacking. When a literature search
based on key words is executed, this has to be taken into
account. For the rat prefrontal cortex we prefer the most
commonly used nomenclature of Krettek and Price [87]. In
a developmental study, Van Eden and Uylings [141] adopted
their nomenclature with the exception of the term medial
precentral area (PrCm) [138]. We use the neutral term Fr2
introduced by Zilles [157] instead. We prefer to use the term
Fr2 rather than PrCm [87], since rats do not have a central
sulcus. Likewise, the term medial agranular area (AGm;
[39]) is not satisfactory, because more cortical areas in the
medial frontal cortex are agranular and the area lateral to
AGm, called lateral agranular area (AGl) is not agranular.
Unfortunately, the nomenclature of Krettek and Price [87]
fortheratprefrontalareasisnotappliedbyPaxinosandWat-
son [110]. In this atlas no distinction has been made between
the infralimbic (IL) and the medial orbital (MO) areas: both

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13
areas are included in MO of Paxinos and Watson [110]. In
addition, they have called the dorsal and ventral anterior cin-
gulate areas (ACd and ACv) the cingulate cortices 1 (CG1),
and 2 (CG2), respectively. We prefer the AC areas, because
these areas have “anterior cingulate” features, which are dif-
ferent from other cingulate areas, see our review above. The
Fr2 area is indicated by Paxinos and Watson [110] as the
secondary motor area (M2). Interestingly, with the sole ex-
ception of the Fr2 area, Swanson [137] in his atlas adopted
the nomenclature of Krettek and Price [87]. In this atlas
Fr2 is indicated instead with the term secondary motor area
(“MOs”). From our review above, it is evident why we sug-
gest to avoid the term secondary motor area (MOs and M2,
respectively).
Please note that besides differences in nomenclature there
are also discrepancies in the delineations of the pertinent
areas: identical names not necessarily imply a similar delin-
eation by different authors. Our cytoarchitectonic definition
of borders of prefrontal areas [138,141] was described in
such a way that they appear reproducible for other PFC re-
searchers. This delineation of the prefrontal cortex is more
or less comparable with the one of Price and coworkers
[87,121]. More specifically, our definition of Fr2 [138,141]
is comparable with the delineation of PrCm by Price and
colleagues. However, the caudal border of ‘our’ Fr2 or
PrCm differs strongly from the Fr2 defined in Zilles [157],
M2 in Paxinos and Watson [110] and MOs in Swanson
[137]. The caudal border of this area defined by Krettek and
Price [87] and Van Eden and Uylings [141] is much more
rostral (i.e. at about −1mm from bregma) than that of the
comparable areas in the atlases of Zilles [157], Swanson
[137] and Paxinos and Watson [110] at about −3.7mm
from bregma). Our caudal border is not only based on cy-
toarchitectonics, but also on the patterns of thalamic and
other connections mentioned above. There are further dif-
ferences in the delineation of the prefrontal cortical areas in
the atlases of Swanson [137] and Paxinos and Watson [110],
but it is outside the scope of this paper to discuss these in
detail.
Acknowledgements
We thank Ms. W.T.P. Verweij for her secretarial assistance
and Mr. H. Stoffels for drawing Figs. 1 and 3.
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