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Netherlands Institute for Brain Research, KNAW, Graduate School Neurosciences, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
b Department of Anatomy, Graduate School Neurosciences, VU University Medical Center, Amsterdam, The Netherlands
c Canadian 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
Woolseys 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.
2003 Elsevier B.V. All rights reserved.
Keywords: Prefrontal cortex; Rat; Primates; Parallel circuits; Basal ganglia; Mesocortical dopaminergic system; Monoamines; Acetylcholine
1. Introduction
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 insular area; AM, anterior medial thalamic nucleus; AO, anterior olfactory
nucleus; BAC, basal amygdaloid complex; cc, corpus callosum; CPm,
caudateputamen complex, medial part; DStr, dorsal striatum; Ent, entorhinal 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 1 mm 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 segment; 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 (supplementary somatosensory cortex) [157]; PC, posterior cingulate area; PC/CL,
paracentral and central lateral thalamic nuclei; PF, parafascicular thalamic 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 compacta; SNr, substantia nigra pars reticulata; SNrdm, dorsomedial part of
SNr; STh, subthalamic nucleus; Te2, area 2 of temporal cortex [157]; TT,
0166-4328/$ see front matter 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2003.09.028
anatomically different subfields [10,23,138], roughly divided in a dorsolateral, a medial and an orbital region [44].
These different subdivisions of the primate prefrontal cortex 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 prefrontal 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 dorsomedial shoulder region) displays features that resemble
characteristics of the primate dorsolateral prefrontal cortex.
Fig. 1. The extent of rats 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.
Fig. 2. Schematic diagrams to illustrate, for the rat brain, the involvement of different parts of the (pre)frontal cortex in various basal gangliathalamocortical
circuits and amygdaloid and midline/intralaminar thalamic circuits. Four basal gangliathalamocortical 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.
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 cortex [5]. All these connectional aspects point to similarities
between prefrontal cortexbasal gangliathalamocortical
circuits of primates and rats. In particular, they show a number 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 connections 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
Fig. 3. A diagram of cortico-cortical connections of the rat prefrontal cortex (modified from [138]). For abbreviations see the Abbreviations section.
across species must be function. One of the major obstacles in comparing the behavior of different species of mammals is that each species has a unique behavioral repertoire
that permits the animal to survive in its particular environmental 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 different 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 behaviors. 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 basic 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 region involved in the integration of sensory and motor information. We can extend Kaass 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
10
References
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]
11
recently, deficits have been shown in various types of attentional 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 production 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 homologous) 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
mPFC lesions in rodents that are equivalent to those observed
in primates with dorsolateral lesions, that the research on the
mPFC of the rat has little to offer to those interested in understanding 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 provide grist for his skepticism. Accordingly, in the past decade
there has been considerable interest in dissociating the different 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 visual 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 Brodmanns areas 6/46
whereas the PL/IL regions are homologous with Brodmanns
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]).
Kesners hypothesis will be a difficult one to unequivocally 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 functions 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 primates [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
12
for odor or taste information (e.g. [4,34,107,117,120]). Furthermore, 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 Schoenbaum 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 reward, 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 respond to the cue as though reward is expected (e.g. [13,46]).
The role of the orbitofrontal cortex in stimulus-reward associations 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 remains 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 regions 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 mammals 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 involved 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 primates 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
5. Conclusions
The present anatomical and functional data indicate that
rats have a prefrontal cortex, in which Fr2 and ACd are incorporated. Preuss and Kaas [114] have stated that evidence
available to them at that time is consistent with the possibility 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 specializations are likely, but dorsolateral-like features, including 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 features. These areas have also features of other type of cortices,
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 Kosmals group from
Warsaw has indicated, that anatomical dorsolateral-like prefrontal 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.
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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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