Do rats have a prefrontal cortex?

Behavioural Brain Research 146 (2003) 3–17

Review

Do rats have a prefrontal cortex? Harry B.M. Uylings a,b,∗ , Henk J. Groenewegen b , Bryan Kolb c a

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 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. © 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, caudate–putamen 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

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 primates 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 comparable with the dorsolateral prefrontal cortex in primates [111,114]. Such a question is complicated, since the rat cortical fields are generally less evoluted, less differentiated 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: [email protected] (H.B.M. Uylings).

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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.

2. Criteria for the definition of a prefrontal cortex For a long time after Brodmann’s studies [17] the prefrontal 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 cytoarchitectonic criterion of having a granular layer IV and a location rostral to the agranular (pre)motor areas. However, comparing different cortical areas in more distantly related 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 easily discernible, respectively) as part of the prefrontal cortex. These are just two examples to emphasize why cytoarchitectonic 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 following 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. electrophysiological and behavioral) properties; (3) the presence and specific distribution of different neuroactive substances and neurotransmitter receptors; (4) the embryological development; and (5) only for closely related species, the cytoarchitectonic 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. Subsequently, we will review comparatively the functional properties 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 thalamocortical projections to the prefrontal cortex, and was therefore viewed as the ‘defining’ nucleus. However, with the advent of more refined anterograde and retrograde tracing techniques, it became apparent that the (prefrontal) cortical 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 ventral 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 nucleus as an important criterion for defining the prefrontal cortex. However, this definition also does not lead to an unambiguous 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 reciprocal 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 cortex 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 position 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], Dermon 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 before, 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 cortical 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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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 ventromedial (VMp) nuclei project quite diffusely and spread out over an extensive region of neocortex (i.e. premotor, supplementary motor area (SMA), supplementary eye field, anterior cingulate (AC) and posterior parietal cortex), but these projections have a relatively higher concentration in the prefrontal 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 ventrolateral 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 topography and the pattern of connectivity of the mediodorsal nucleus 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 projecting 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 distinguished caudal AGm from mid and rostral AGm, and showed that rostral and mid AGm receives thalamic afferents 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 −1 mm 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 suppose 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 electrophysiological 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 regions showing considerable overlap of connections from various thalamic nuclei, which of these thalamic nuclei provides 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 different 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 organization in the frontal cortical–basal ganglia connections and in the basal ganglia–thalamic projections. This topographical 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] identified 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 midline/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 primates, 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 cortex [5]. All these connectional aspects point to similarities between prefrontal cortex–basal ganglia–thalamocortical 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

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[108,142]. In both rats and primates the prefrontal cortex is extensively connected with different cortical areas such as premotor, somatosensory, auditory, visual, olfactory, gustatory 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 reciprocal and that such connections exist preferentially between cortical areas with a similar level of cytoarchitectonic differentiation. 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 et al. [12] showed that the cytoarchitectonically less differentiated prefrontal regions have fewer specific cortico-cortical connections. They receive projections from two or more cortical areas representing different sensory modalities together with a substantial input from limbic cortices. The cytoarchitectonically more highly differentiated (thus eulaminate or strongly granular) prefrontal areas receive more specific projections representing only one or two different modalities, and relatively few projections from limbic cortices. 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 information 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 strengthened 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, however, the property of a multimodal association area in a hierarchical 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 cortices 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 anterograde labeling) that Fr2 and ACd receive more projections from somatosensory and associational visual cortices than from the primary motor cortex. The macaque prefrontal cortex 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 possible. The data available indicate extensive, reciprocal connections 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’ region (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 prefrontal cortex (i.e. agranular insular cortices), have reciprocal 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 prefrontal cortex has reciprocal connections with motor, mixed somatosensory-motor, and somatosensory association cortices. Thus, premotor characteristics appear to coincide here with prefrontal characteristics [138]. The ‘dorsal shoulder’ region has reciprocal connections mainly with visual cortices and the retrosplenial cortex. As mentioned above the caudal part of the dorsal shoulder region appears to incorporate features of the frontal eye field. It is of interest to note that Fuster [44,45] views the interactions 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, uncertainty or ambiguity, and has to span time intervals with short-term or working memory. These functional connections disappear or weaken when the action becomes automatic. 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 systems together with prefrontal cortico-cortical connections 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 cortical projections to the locus coeruleus derive from the medial PFC and the agranular insular PFC areas, while the cortical

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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 entorhinal cortex, whereas only the prefrontal cortex (both medial and agranular insular PFC) projects back to the dopaminergic neurons in ventral tegmental area (VTA or A10) [25] and the dopaminergic pars compacta of the substantia nigra (A9). The rat prefrontal cortex receives distinct parallel 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 tegmental area [89,91]. The ventral tegmental area is the origin of the major dopaminergic input in the rat prefrontal cortex 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 restricted 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 ventromedial 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 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 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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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 surprisingly good and the tuning characteristics of visual neurons is strikingly similar to that of larger-brained mammals. Similarly, rats and cats have a large somatosensory representation 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 tactile sensations. Thus, both the visual and tactile recognition of objects are class-common functions, even though the details of this recognition may vary in a species-typical manner. 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 apparent from the work of Whishaw et al. [148,149] that the capacity 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 comparisons of frontal lobe function between primates and rodents, 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 behavior, 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 identification of food items using visual, tactile, and olfactory information. But the sensory world has far more information 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 information 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 function 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 functionally 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 monitoring 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 processing of olfactory and gustatory information, and in spontaneity (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 initiation (e.g. [36]). In addition, all three areas probably produce 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, attentional 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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In monkeys the symptoms of lesions to the dorsolateral prefrontal, orbitofrontal, and anterior cingulate regions respectively produce analogous behavioral deficits to those observed in humans. In particular, dorsolateral lesions especially 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 disinhibition of motor behaviors, abnormalities in social-affective behaviors, deficits in certain types of olfactory and gustatory 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 retention, 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 different 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 impairment

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]

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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 Brodmann’s areas 6/46 whereas the PL/IL regions are homologous with Brodmann’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 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

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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

reviewed above, it is likely that these latter areas are also subdivided. If this is so, then it is likely that the primitive 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 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 Kosmal’s 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.

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]. Unfortunately, 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] for the rat prefrontal areas is not applied by Paxinos and Watson [110]. In this atlas no distinction has been made between the infralimbic (IL) and the medial orbital (MO) areas: both

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areas are included in MO of Paxinos and Watson [110]. In addition, they have called the dorsal and ventral anterior cingulate 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 different 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 exception 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 suggest 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 delineation 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 researchers. 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 −1 mm from bregma) than that of the comparable areas in the atlases of Zilles [157], Swanson [137] and Paxinos and Watson [110] at about −3.7 mm from bregma). Our caudal border is not only based on cytoarchitectonics, but also on the patterns of thalamic and other connections mentioned above. There are further differences 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.

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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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