Do Rats Have a Prefrontal Cortex

8/16/2019 Do Rats Have a Prefrontal Cortex

1/15

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 ca Netherlands Institute for Brain Research, KNAW, Graduate School N eurosciences, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands

b Department of Anatomy, Graduate School Neurosciences, VU University Medical Center, Amsterdam, The Netherlandsc 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, controversialviews 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 andWoolsey’s ‘prefrontal cortex’ definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsalthalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomicaland functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about thenature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functionalcharacteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortexthat includes notonly features of themedial and orbital areas in primates,but also some features of theprimate dorsolateralprefrontal cortex.© 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 cingulatearea; ACv, ventral anterior cingulate area; AId, dorsal agranular insulararea; AIp, posterior agranular insular area; AIv, ventral agranular insu-lar area; AM, anterior medial thalamic nucleus; AO, anterior olfactorynucleus; 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, frontalcortical areas 1 and 3, according to Zilles [157]; Fr2, frontal cortical area2, rostral to about −1 mm from bregma; GPe, globus pallidus, externalsegment; 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, medialorbital 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 partof 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, rhinalsulcus; RSA, agranular retrosplenial cortex; RSG, granular retrosplenialcortex; 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 ahundred times smaller than that of the cerebral cortex of macaques, and about a thousand times smaller than thatof 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 notsurprising that discussions are ongoing about whether ornot particular cortical areas in the rat brain are comparablewith specific cortical areas in primates. Recently this issuehas 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 ratcortical fields are generally less evoluted, less differenti-ated and less segregated than those in the primate cerebralcortex. The primate prefrontal cortex consists of various

taenia tecta; VA, ventral anterior thalamic nucleus; VL, ventral lateralthalamic nucleus; VLO, ventrolateral orbital cortical area; VM, ventralmedial thalamic nucleus; VMm, medial part of VM; VO, ventral orbitalcortical 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).

0166-4328/$ – see front matter © 2003 Elsevier B.V. All rights reserved.doi:10.1016/j.bbr.2003.09.028


2/15

4 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 andemotion functions [8,12,31,44,99]. It is generally acceptedthat the prefrontal cortex is involved in different aspects

of executive control and that the neuronal basis for thesefunctions is formed by the extensive neuronal networks inwhich the prefrontal cortex is intricately involved. AlthoughPreuss [111] did not question the existence of a rat pre-frontal cortex in general, this was the way it was perceivedby many primate researchers. However, Preuss [111] andPreuss and Kaas [114] questioned explicitly the existence of an equivalent of the primate dorsolateral prefrontal cortexin non-primate species. To answer the question whether ratshave a dorsolateral-like prefrontal cortex we must considervarious anatomical and functional criteria that define thedifferent prefrontal regions. On the basis of the structuraland 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 resemblecharacteristics 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 speciesand called the ‘frontal granular cortex’ [14]. The definitionof 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 criteriaappeared to be untenable. For example, the primary motorcortex in rats is considered to be homologous to the one inmonkeys [105], but this cortical area is agranular in matureprimates and granular in rats. Likewise, Barbas and Pandya[10] consider limbic cortices in primate brains, which areagranular 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 seekinghomologies between different brain areas in more distantlyrelated species. It is now generally accepted that the follow-ing criteria have to be taken into account when discussinghomologies between cortical areas in different species: (1)the pattern of specific connections and the relative densityof these connections; (2) the functional (i.e. electrophys-iological and behavioral) properties; (3) the presence andspecific distribution of different neuroactive substances andneurotransmitter receptors; (4) the embryological develop-ment; and (5) only for closely related species, the cytoarchi-tectonic characteristics. The greater the similarities betweenthe characteristics, the more likely it is that brain regionsare homologous. In the following account we will employ

the first three criteria for comparing prefrontal cortical areasin primates and rats. These three criteria also were appliedby Preuss [111]. From this perspective we will consider theconnections of the rat and primate prefrontal cortices withthalamic, basal ganglia, cortical, limbic and monoaminergicstructures, 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 corticaldifferentiation and specialization (e.g. [90]). The reciprocalconnections of the major thalamic nuclei are therefore usedto define cerebral cortical areas. At the time of Rose andWoolsey [126], the mediodorsal nucleus of the thalamus

was assumed to be the only nucleus with thalamocorti-cal projections to the prefrontal cortex, and was thereforeviewed as the ‘defining’ nucleus. However, with the ad-vent of more refined anterograde and retrograde tracingtechniques, it became apparent that the (prefrontal) cor-tical areas that receive mediodorsal thalamic input alsoare connected with other thalamic nuclei. Thalamic nucleiother than the mediodorsal nucleus that reach the prefrontalcortex include the intralaminar and midline nuclei, theanterior 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 asthe premotor, motor, temporal and parietal cortices, as hasbeen 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 prefrontalcortex. 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 onlythose cortical areas in the prefrontal cortex for which thereciprocal connections with the mediodorsal nucleus (MD)are stronger (i.e. in terms of a higher number of projectingneurons 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, hasled us to include the primate and rat anterior cingulate cor-tex in the prefrontal cortex [138]. This approach in definingthe prefrontal cortex is strengthened by the recent analysisof Kötter, who demonstrated the special, predominant posi-tion of the mediodorsal nucleus for the macaque prefrontalcortex on basis of multidimensional scaling analysis of the thalamoprefrontal cortical projections (Kötter, personalcommunication, 2003). In addition, Barbas et al. [11], Der-mon and Barbas [35] and Ray and Price [122] showed in


3/15

H.B.M. Uylings et al. / Behavioural Brain Research 146 (2003) 3–17 5

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 anatomicaltechniques. Fine dots indicate the area described by Leonard [88], large dots the extension described by Krettek and Price [87], oblique lines the extensionproposed 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 ratanterior insular area. (C) The view illustrated by Preuss and Kaas [114], modified from Preuss [111], in which ACd is now incorporated in the anteriorcingulate 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) formthe 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 neuronsprojecting to the prefrontal cortex, as it has been defined be-fore, are located in the mediodorsal nucleus. This also goesfor the rat prefrontal cortex (see Fig. 1) [54,87,123,140].

Dermon and Barbas [35] reported that area 25 inmacaques (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 fromthe mediodorsal nucleus. When this is also true for theefferent corticothalamic projections from area 25, thenmacaque area 25 should probably not be included in theprefrontal cortex [12]. A similar situation holds likelyfor the ventrolateral orbital cortical area (VLO) in the rat[54,123,155].


4/15


For a further comparison of monkey and rat thalamic datait is important to know that in non-human primates thalamicventral nuclei have a differential cortical projection patternfor 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 theseprojections have a relatively higher concentration in the pre-frontal cortex. In contrast, the anterior ventrolateral (VLa)cortical projections are more concise and concentrated inpremotor and SMA areas, with additional lesser projectionsalso to the motor area. In addition, the posterior ventrolat-eral nucleus (VLp) is the principal source of projections toprimary 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 dueto its difficult cytoarchitectonic delineation [56,65,138].

In the last decade the inclusion of the rat frontal area2 (Fr2) and the dorsal anterior cingulate area (ACd) (seeFig. 1) in the prefrontal cortex has been disputed by Preuss[111] and Condé et al. [28,29]. The results of Condé et al.’sretrograde tracer studies on thalamic afferents [28] andcortico-cortical afferents [29] to rat medial frontal cortexwere decisive for their and Preuss’ thesis, namely that therat Fr2 (also called the precentral medial area (PrCm) oragranular medial cortex (Agm), see below) and the rat ACdare 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. Condéet al. [28] described in their retrograde tracer study thatonly a few neurons from the mediodorsal thalamic nucleusproject to Fr2 and ACd and that a higher number of thalamicprojecting neurons are positioned in the intralaminar, theventrolateral (VL) and ventromedial (VM) nuclei. In thisrespect, their Fig. 12 [28] is conspicuous for illustrating acase with a relatively high number of MD neurons project-ing to ACd. Furthermore, several groups [54,87,121] haveobserved in extensive anterograde and retrograde tracingstudies that the rat Fr2 and ACd (Fig. 1) have a very densereciprocal connection with the paralamellar or ventrolateralsegment of the thalamic mediodorsal nucleus. This can alsobe concluded from the anterograde and retrograde tracerstudies of Reep and Corwin [124], which were directedespecially to the Fr2 (their AGm). Reep and Corwin dis-tinguished caudal AGm from mid and rostral AGm, andshowed that rostral and mid AGm receives thalamic affer-ents from a higher number of neurons in the mediodorsalnucleus. It appeared that only the caudal AGm has afferentsfrom cells mainly located in VL and only a few neurons inthe mediodorsal nucleus. However, this part of AGm or Fr2[156] is not included in the rat prefrontal cortex as definedby Krettek and Price [87], Groenewegen [54], Uylings and

Van Eden [138], and Van Eden et al. [142], because it iscaudal to about −1 mm from bregma (see also note below).In addition, Vertes [143] showed that both ACd and Fr2have strong projections particularly to the MD. Therefore,we conclude that ACd and Fr2 have a more prefrontal thanpremotor 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 ACdincorporates a zone homologous to the macaque frontal eyefield (FEF) [138,142]. This is corroborated by electrophys-iological studies [59,104] and by unilateral lesion studiescausing multimodal neglect [73,95].

We realize the pitfalls of the quantitative definition of ouranatomical ‘prefrontal cortex’ definition. Even with the useof modern neuroanatomical tracing techniques, it is ratherdifficult to determine unequivocally for those cortical re-gions showing considerable overlap of connections fromvarious thalamic nuclei, which of these thalamic nuclei pro-vides the strongest connections. For example, comparison

of numbers [139] of different types of neurons projecting toa particular cortical area with retrograde tracing implies theassumption that the extent of these axonal terminal fields issimilar in the different regions that have been injected witha particular tracer. This is not always the case, however. Itis therefore important to consider in addition the quality of connections (e.g. ‘driver’ and ‘modulator’ type of thalamicconnections [56,132]), the cortico-cortical and subcorticalneuronal networks and functional properties in which dif-ferent prefrontal cortical areas have a particular, differentposition.

3.2. Prefrontal cortex–basal ganglia relationships

The frontal lobe as a whole has a special relationshipwith the basal ganglia in that it is the part of the cerebralcortex that receives the main input from the basal ganglia,through a relay in the thalamus [97]. This basal gangliainfluence has long been known for the motor and premotorcortices, but the frontal areas anterior to the (pre)motorcortices (i.e. mostly the prefrontal cortical areas) are notexcepted from this particular subcortical influence. Like thefrontal cortex, the parietal, occipital and temporal corticesall project to the basal ganglia, in particular the striatum, butthese posteriorly located cortices do not receive informationback from the basal ganglia, with the exception of area TEin the inferotemporal cortex [96]. A particular subset of thalamic nuclei (i.e. the mediodorsal, ventromedial, ventralanterior and, to a lesser degree, the ventral lateral nuclei)form the essential link between the pallidum and substantianigra pars reticulata, as the output structures of the basalganglia [2,58,94,98] and the (pre)frontal cortex. It is alsorelevant to emphasize the high degree of topographical or-ganization in the frontal cortical–basal ganglia connectionsand 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


5/15


Fig. 2. Schematic diagrams to illustrate, for the rat brain, the involvement of different parts of the (pre)frontal cortex in various basal ganglia–thalamocorticalcircuits and amygdaloid and midline/intralaminar thalamic circuits. Four basal ganglia–thalamocortical circuits are depicted with similar organizationalcharacteristics. Compare also the organization of similar circuits in primates [2]. All four circuits involve different parts of the (pre)frontal cortex, the dorsalor ventral striatum, the pallidal and nigral complex and the ventral and medial thalamic nuclei. The present diagram emphasizes the ‘closed’ characterof 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 thedorsal striatum, together with the absence of the amygdala connections. (B) ‘Dorsal shoulder prefrontal’ circuit (Fr2 and ACd): the cortical and striatal waystations 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 amygdaloidcomplex are strongly involved in this particular circuit. (D) ‘Lateral prefrontal/agranular insular’ circuit (AIv/AId): the intermediodorsal thalamic nucleusand the anterior part of the basal amygdaloid complex project to the cortical and striatal way stations of this circuit. For a comparison with the circuitsdescribed in primates, it is important to note that the topography of subcortical afferents and thalamocortical efferents of the thalamic mediodorsal nucleusin rats and primates is largely similar [56]. The medial (and central) segments of the rat mediodorsal nucleus resemble the magnocellular part of theprimate 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 identifiedboth 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 ‘lateralorbitofrontal’, and a ‘dorsolateral’ prefrontal circuit, whichare 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 theprefrontal cortex and the basal ganglia are involved concernthe specific relationships of the projections from the mid-line/intralaminar thalamic complex as well as the amygdalaand, to a lesser extent the hippocampus, to the cortical andstriatal relay stations in the basal ganglia–thalamocorticalcircuits (Fig. 2) [9,55,57,58,93,144]. In both rats and pri-mates, the circuits that involve the prefrontal cortical areasare characterized by amygdaloid inputs. However, in rats

the dorsal anterior cingulate (ACd) and Fr2 areas receive theleast amygdaloid fibers of the prefrontal areas [57], whilealso in nonhuman primates the dorsolateral prefrontal cortexhas the weakest amygdaloid input in the prefrontal cor-tex [5]. All these connectional aspects point to similaritiesbetween prefrontal cortex–basal ganglia–thalamocorticalcircuits of primates and rats. In particular, they show a num-ber of comparable features for both the primate dorsolateralprefrontal 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 arepredominantly ipsilateral [1,54,108,142]. The majority of terminal axons in the prefrontal cortex are cortical afferents


6/15


[108,142]. In both rats and primates the prefrontal cortex isextensively connected with different cortical areas such aspremotor, somatosensory, auditory, visual, olfactory, gus-tatory and limbic cortical areas [7,24,26,142]. Pandya andYeterian [108] showed that in macaques the connectionsbetween the prefrontal and other cortical areas are recipro-

cal and that such connections exist preferentially betweencortical areas with a similar level of cytoarchitectonic differ-entiation. However, connections between distinct prefrontalcortical areas exist both between areas with similar levelsof cytoarchitectonic differentiation as well as between areaswith different levels of differentiation. In addition, Barbaset al. [12] showed that the cytoarchitectonically less differen-tiated prefrontal regions have fewer specific cortico-corticalconnections. They receive projections from two or morecortical areas representing different sensory modalities to-gether with a substantial input from limbic cortices. Thecytoarchitectonically more highly differentiated (thus eu-laminate or strongly granular) prefrontal areas receive more

specific projections representing only one or two differentmodalities, and relatively few projections from limbic cor-tices. In primates, in particular the macaque, the dorsolateralprefrontal 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 bedrawn. As mentioned above the retrograde tracer study oncortico-cortical afferents of Condé et al. [29] has strength-ened the view of Condé et al. and Preuss [111] that the ratFr2 and ACd is largely a premotor cortex and do not belongto the prefrontal cortex. By excluding this ‘dorsal shoulder’

region from the rat prefrontal cortex, they arrived to theiropinion, that the prefrontal cortex in rats lack features of theprimate dorsolateral prefrontal cortex [29,111]. Condé et al.[29] concluded that Fr2 and ACd have the main featuresof a premotor cortex and “none of the features of any areaof the macaque prefrontal cortex”. A typical feature of themacaque 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 nodalstation in several distributed parallel networks [26,52,113].Like the macaque prefrontal cortex, the rat prefrontal cortexreceives 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 bea 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 projectionsfrom somatosensory and associational visual cortices thanfrom the primary motor cortex. The macaque prefrontal cor-tex has the strongest connections with posterior parietal andtemporal association areas [26,27]. Rat equivalents are notwell described for these parietal and temporal associationareas [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 reciprocalcortico-cortical connections reveal at least three subfields inthe rat medial prefrontal cortex, i.e. a ‘dorsal shoulder’ re-gion (Fr2 and ACd); a rostral part of the medial prefrontalcortex; 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 hippocampalformation [57,62,145]. The rostral part of the rat medial pre-frontal cortex has reciprocal connections with motor, mixedsomatosensory-motor, and somatosensory association cor-tices. Thus, premotor characteristics appear to coincide herewith prefrontal characteristics [138]. The ‘dorsal shoulder’region has reciprocal connections mainly with visual cor-tices and the retrosplenial cortex. As mentioned above thecaudal 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 contextof ‘perception–action cycle’. This is a hierarchical concepttoo. The prefrontal cortex and other cortices are functionallyconnected for as long as the behavior contains novelty, un-certainty or ambiguity, and has to span time intervals withshort-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 transmittersystems together with prefrontal cortico-cortical connectionsin primates and rats also show the unique gating position of the prefrontal cortex.

In both rats and primates the entire neocortex receivescholinergic innervation from the basal forebrain nuclei. Theprefrontal cortex, in addition, gets cholinergic fibers fromthe laterodorsal tegmental nucleus. Likewise in both species,the prefrontal cortex (in primates mainly the orbital andmedial PFC and in rats mainly the medial PFC) is the onlycortical region that has direct projections back to these basalforebrain and brainstem nuclei [48,49,57,127,138,156].

The noradrenergic fibers from the locus coeruleus and theserotonergic fibers from the dorsal and median raphe nucleiare widely distributed over almost the entire neocortex. Alsowith respect to these transmitter systems in both rats andprimates certain prefrontal areas are the only cortical areasthat project back to the locus coeruleus and to the dorsal andmedian raphe nuclei. In primates the cortical projections tothe noradrenergic locus coeruleus and the serotonergic raphenuclei derive from the dorsolateral PFC [6]. In rats the corti-cal projections to the locus coeruleus derive from the medialPFC and the agranular insular PFC areas, while the cortical


7/15


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 fromthe medial PFC, especially its ventral part [60,63,64,138].

In rats, the cortical terminal fields of dopaminergic fibersare mainly restricted to the prefrontal areas and the entorhi-nal cortex, whereas only the prefrontal cortex (both medialand 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 cingulatecortex receives dopaminergic fibers in the superficial layers

from the pars compacta of the substantia nigra and in thedeeper layers from the lateral part of the ventral tegmen-tal area [89,91]. The ventral tegmental area is the originof the major dopaminergic input in the rat prefrontal cor-tex and different parts of the ventral tegmental area appearto project to different prefrontal areas [69]. Particularly inprimates, cortical dopaminergic fibers appear not to be re-stricted to the prefrontal cortex. As suggested [47,138] thisappears to be caused mainly by extension of dopaminergicmidbrain cellular groups such as the retrorubral areas A8and A9 [152]. Direct recurrent projections from the primatedorsolateral prefrontal cortex to the medial substantia nigrapars compacta (A9) have been reported [89], but they canalso be expected to project to the ventral tegmental area onthe basis of the above.

In rats the histaminergic neurons in the tuberomammillaryhypothalamic region have reciprocal connections with ven-tromedial prefrontal cortex [154]. These connections havenot 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 repertoirethat permits the animal to survive in its particular environ-mental niche. There is therefore the danger that neocorticalorganization is uniquely patterned in different species in away that reflects the unique behavioral adaptation of differ-ent species. One way to address this problem is to recognizethat 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 becapable of learning complex tasks under various schedulesof reinforcement (e.g. [146]). The details and complexity of these behaviors clearly vary, but the general capacities arecommon to all mammals. Warren and Kolb [146] proposedthat behaviors and behavioral capacities demonstrable inall mammals could be designated as class-common behav-iors. In contrast, behaviors that are unique to a species andthat have presumably been selected to promote survival in aparticular niche are designated as species-typical behaviors.This distinction is important because it has implications forthe organization of the cerebral cortex.

Kaas [68] has argued, for example, that all mammalianspecies have similar regions devoted to the analysis of ba-sic sensory information (e.g. primary visual (V1), primaryauditory (A1), and primary somatosensory (S1) areas), thecontrol 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 theseregions have class-common functions. To be sure, there arelarge species differences in the details of the class-commonbehaviors. Monkeys (and humans) have chromatic visioncompared to the largely achromatic vision of cats or rats.Nevertheless, in all mammalian species studied, removal of


8/15


visual cortex severely disrupts object recognition. Indeed,although the visual cortex of the rat has often been portrayedas 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 haveno such representation but in all species the somatosensorycortex functions to represent skin-related receptors for tac-tile sensations. Thus, both the visual and tactile recognitionof 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 allmammals have a motor map (e.g. [153]) in which the relativemotor facility of different body regions is reflected by thesize of the motor representation. Curiously, although thereare clear interspecies differences in the capacity to use theforelimbs 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 cerebralorganization of this control, is strikingly similar betweenrodents and primates. Indeed, recent taxonomic studies of mammalian evolution have noted that rodents and primatesare more closely related than had been realized previously.For example, they are more related than cats and primatesare [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 isto 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 cortexof mammals developed because all mammals face commonfunctional problems related to the organization of behav-ior, then we should be able to identify these functions. Oneplace to begin searching for class-common frontal functionsis to consider what animals use sensory inputs for. The mostobvious function is to guide behavior on line, such as inthe visuomotor control of movements in space or the iden-tification of food items using visual, tactile, and olfactoryinformation. But the sensory world has far more informa-tion available than the brain can handle at one time so theremust be some system to select information as well as tofocus and maintain attention. Similarly, although behaviorcan be directed to sensory stimuli on-line, it can also berelated 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 impliesa short-term erasable storage of information, or by a type of long-term memory system in which information is stored foran extended time. In both instances the stored informationis used to select and generate behavior that is appropriatefor the particular context. The behaviors that are generatedmay be novel, and directly related to the sensory events, orthey may be preprogrammed in chains that are innate butstill must be selected with respect either to ongoing sensory

information or to internal states. Thus, there must be sometype of master (sometimes referred to as executive) controlsystem that selects behavior. It is our contention that theclass-common function of the prefrontal cortex is to selectand generate behavior patterns. In addition, it is proposedthat 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 generalview of prefrontal functioning is hardly novel (see reviews[44,52,78,109]), it is the idea that a prefrontal system withsuch functions will be found in all mammals that is the keyconcept in the current discussion.

One prediction from our general hypothesis is that allmammals with damage to the prefrontal homologue shouldshow functional disruptions of the same general sort. Theprefrontal cortex is extensive in most mammals, however, sowe might also anticipate that there will be some subdivisionof functions across the prefrontal regions in different species[138]. The organization of the subdivisions is likely to have

some species-typical characteristics, however. Consider, forexample, the relative importance of vision to the control of forelimb movement in primates versus a parallel olfactorycontrol of forelimb movement in the rat (e.g. [148]). Suchdifferences would be expected to be reflected in differencesin the subtle organization of the prefrontal subregions. Weshall review first the evidence for general symptoms of prefrontal injury in the major subdivisions of primates androdents, and then consider the issue of how to comparefunctions 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, thereare the dorsolateral frontal region, the lateral orbitofrontalregion, and an anterior cingulate/medial orbitofrontal region.Damage to the dorsolateral frontal region is characterizedespecially by deficits in working memory, particularly as itrelates to certain executive processes such as the monitor-ing and planning of behaviors (e.g. [44,129]). Damage tothe orbitofrontal frontal region is characterized by alteredsocio-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 cingulateregion is not as well characterized, but can include reducedresponse 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 theattentional domain remain unclear and are likely related tothe type of sensory information being processed. Thus, at-tentional processes related to olfactory and gustatory inputsare likely related to orbitofrontal regions, those related tovisual inputs are likely related to dorsolateral regions, andthose related to internal states (such as pain) are related toanterior cingulate regions.


9/15


In monkeys the symptoms of lesions to the dorsolateralprefrontal, orbitofrontal, and anterior cingulate regions re-spectively produce analogous behavioral deficits to thoseobserved in humans. In particular, dorsolateral lesions espe-cially produce deficits in working memory, whereas lesionsthat 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-affectivebehaviors, deficits in certain types of olfactory and gusta-tory processing, and in the association between reward andexternal cues (e.g. [125]). Cingulate lesions lead to deficitsin the encoding of movements (including eye movements),and reduced response to pain. Although an early studysuggested that cingulate lesions produce deficits in delayedalternation, this is only seen in acquisition and not in reten-tion, which is rather different than the effect of dorsolaterallesions (e.g. [115]).

4.2. Effects of frontal lesions in rats

It was demonstrated in the early 1970s that lesions to themedial and lateral orbital regions in rats produced very dif-ferent behavioral syndromes, and that these changes werestrikingly similar to those observed in primates with lesionsto the dorsolateral and orbitofrontal regions, respectively(Table 1; for reviews see [78,79]). For example, damage tothe medial prefrontal (mPFC) area produces severe deficitsin acquisition and retention of working memory tasks suchas 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 1Summary of the effects of mPFC and OFC lesions in rats

Behavioral impairment References

mPFCVisual working memory [86]Strategy formation [85]Spatial reversal [38,86]Habituation [74,76]Skilled reaching [149]Motor sequencing [80]Attention [18,102]Attention set shift [16]

Food hoarding [75]Fear extinction [116]Conditioned emotional responses [42,43]Operant reversal learning [33,41]Conflict behavior [20]Operant working memory [19]

OFCHyperactivity [74]Social behavior [32,77]Incentive association [46]Odor working memory [107]Configural odor learning [150]Odor reversal learning [128,131]Feeding [75]

recently, deficits have been shown in various types of atten-tional tasks [102] and in a task requiring a reversal or a shiftof 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 thatrequire 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 bymany as convincing evidence of parallel (and perhaps ho-mologous) functions in rodents and primates, Preuss [111]remained unconvinced. Indeed, he has argued that in viewof what he believed to be significant anatomical differences,and the failure to find prolonged or long-lasting deficits aftermPFC lesions in rodents that are equivalent to those observedin primates with dorsolateral lesions, that the research on themPFC of the rat has little to offer to those interested in un-derstanding frontal lobe functioning in primates. Preuss waswrong on his conclusion that rats with medial frontal do nothave significant memory deficits (e.g. [85,86]), but the fact

that most studies of medial frontal function had made lesionsincluding all of the medial prefrontal subregions did pro-vide grist for his skepticism. Accordingly, in the past decadethere has been considerable interest in dissociating the dif-ferent medial prefrontal subregions in the rat. It has nowbecome clear that the dorsal anterior cingulate region, andprelimbic/infralimbic region can be functionally dissociated[51,60a]. In general, it appears that the PL region is involvedin attentional and response selection functions as well as vi-sual working memory (e.g. [53]) whereas the more dorsalregions (ACd) are involved with generating rules associatedwith 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 anteriorcingulate region is homologous to Brodmann’s areas 6/46whereas the PL/IL regions are homologous with Brodmann’sareas 45 and 47. Additionally, although less is known aboutits precise role in behavior, it appears that the IL regionplays a special role in autonomic control, and especially inthe 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 currentargument, which is simply that the medial frontal regionshave class-common functions that are similar to those of thedorsolateral and possibly cingulate regions in the monkeyfrontal lobe. We suggest that these class-common functionsinclude functions that are often referred to as executive func-tions in primates. These functions would include workingmemory, the selection of information (often referred to asattention), and the shifting of attention from one stimulusattribute to another (e.g. [21]).

There is much more parsimony in reviews comparing theeffects of lateral orbitofrontal lesions in rodents and pri-mates [130]. The lateral orbital region receives significantolfactory and taste input and although lateral orbital lesionsdo not produce deficits in olfactory or taste discriminations,they do produce deficits in tasks requiring working memory


10/15


for odor or taste information (e.g. [4,34,107,117,120]). Fur-thermore, lesions to the lateral orbital region disrupt thelearning of cross-modal associations that involve odor ortaste cues (e.g. [150]). More recently, studies by Schoen-baum and his colleagues (e.g. [46,131]) have emphasizeda role of the orbital cortex in the encoding of the acquired

incentive value of cues. For example, both rats and primatescan show intact performance on discriminations that requireresponding to neutral cues (such as a light) that predicts re-ward, while at the same time showing marked deficits whenthe incentive value of the stimulus is reduced. Such deficitscan 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 tuningcharacteristics of neurons in the orbital region of both ratsand monkeys [130]. Finally, damage to the orbitofrontalcortex 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 aclass-common function related to making higher order useof olfactory and taste information. This can be seen easilyin tests that require the association of such information withevents in the world, whether they are learned associationssuch as neutral cues and reward or natural stimuli (such asconspecific odors) or rewards that may be more abstract(such as social bonding). Although odors obviously play areduced 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 ventralorbital area (but see [30]). We noted earlier that this regionhas ambiguous anatomical characteristics so at present wemust 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 thereis a strong convergence of class-common symptoms acrossmammals. 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 controlof socioaffective behaviors, a “dorsolateral-like” area in-volved especially in working memory, and an “anterior cingulate-like” area concerned primarily with visceromotorbehaviors and some forms of motor sequencing. To be sure,there are likely to be significant cross species differencesin 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 regionof frontal cortex that can be defined both anatomically andfunctionally as prefrontal cortex. Further, it is likely that theprefrontal cortex is subdivided into at least an “orbital-like”and another region that may include both “dorsolateral- andanterior cingulate-like” features. Finally, given the anatomy

reviewed above, it is likely that these latter areas are alsosubdivided. If this is so, then it is likely that the primi-tive mammals that gave rise to extant mammals had a moreor less subdivided prefrontal cortex that evolved to solveclass-common behavioral problems.

5. Conclusions

The present anatomical and functional data indicate thatrats have a prefrontal cortex, in which Fr2 and ACd are in-corporated. Preuss and Kaas [114] have stated that evidenceavailable to them at that time “is consistent with the pos-sibility that the dorsolateral prefrontal cortex is a primatespecialization”. Certainly, the rat prefrontal cortex is not asdifferentiated 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. 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 cortexareas are to the premotor cortex the more premotor featuresthey have.

We focus in this review on rats, but Kosmal’s group fromWarsaw 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 conclusionthat the dorsolateral prefrontal regions of primates are not aunique specialization.

6. Note on prefrontal nomenclature

A stable and unequivocal nomenclature is desired [110],although neuroanatomical nomenclature should remainflexible in order to incorporate new insights [137]. Unfortu-nately, a generally accepted nomenclature for the prefrontalcortical areas in rats is still lacking. When a literature searchbased on key words is executed, this has to be taken intoaccount. For the rat prefrontal cortex we prefer the mostcommonly used nomenclature of Krettek and Price [87]. Ina developmental study, Van Eden and Uylings [141] adoptedtheir nomenclature with the exception of the term medialprecentral area (PrCm) [138]. We use the neutral term Fr2introduced by Zilles [157] instead. We prefer to use the termFr2 rather than PrCm [87], since rats do not have a centralsulcus. Likewise, the term medial agranular area (AGm;[39]) is not satisfactory, because more cortical areas in themedial frontal cortex are agranular and the area lateral toAGm, 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 Wat-son [110]. In this atlas no distinction has been made betweenthe infralimbic (IL) and the medial orbital (MO) areas: both


11/15


areas are included in MO of Paxinos and Watson [110]. Inaddition, 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, becausethese 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 thesecondary motor area (M2). Interestingly, with the sole ex-ception of the Fr2 area, Swanson [137] in his atlas adoptedthe nomenclature of Krettek and Price [87]. In this atlasFr2 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 thereare also discrepancies in the delineations of the pertinentareas: identical names not necessarily imply a similar delin-eation by different authors. Our cytoarchitectonic definitionof 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 moreor 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 andcolleagues. However, the caudal border of ‘our’ Fr2 orPrCm 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 andPrice [87] and Van Eden and Uylings [141] is much morerostral (i.e. at about −1 mm from bregma) than that of thecomparable areas in the atlases of Zilles [157], Swanson

[137] and Paxinos and Watson [110] at about −3.7 mmfrom bregma). Our caudal border is not only based on cy-toarchitectonics, but also on the patterns of thalamic andother connections mentioned above. There are further dif-ferences in the delineation of the prefrontal cortical areas inthe atlases of Swanson [137] and Paxinos and Watson [110],but it is outside the scope of this paper to discuss these indetail.

Acknowledgements

We thank Ms. W.T.P. Verweij for her secretarial assistanceand Mr. H. Stoffels for drawing Figs. 1 and 3.

References

[1] Akert K, Hartmann-Von Monakov K. Relationships of precentral,premotor, and prefrontal cortex to the mediodorsal and intralami-nar nuclei of the monkey thalamus. Acta Neurol Exp 1980;40:7–25.

[2] Alexander GE, Crutcher MD, DeLong MR. Basal ganglia–thalamocortical circuits: parallel substrates for motor, oculomotor,‘prefrontal’ and ‘limbic’ functions. In: Uylings HBM, Van EdenCG, De Bruin JPC, Feenstra MPG, editors. The prefrontal cortex:

its structure, function and pathology. Progress in brain research,vol. 85. Amsterdam: Elsevier; 1990. p. 119–46.

[3] Alexander GE, DeLong MR, Strick P. Parallel organization of func-tionally segregated circuits linking basal ganglia and cortex. AnnRev Neurosci 1986;9:357–81.

[4] Alvarez P, Eichenbaum H. Representations of odors in the rat or-bitofrontal cortex change during and after learning. Behav Neurosci2002;116:421–33.

[5] Amaral DG, Price JL. Amygdalo-cortical projections in the monkey( Macaca fascicularis). J Comp Neurol 1984;230:465–96.

[6] Arnsten AFT. Catecholamine regulation of the prefrontal cortex. JPsychopharmacol 1997;11:151–62.

[7] Barbas H. Architecture and cortical connections of the prefrontalcortex in the rhesus monkey. Adv Neurol 1992;57:91–115.

[8] Barbas H. Anatomic basis of cognitive–emotional interactions in theprimate prefrontal cortex. Neurosci Biobehavior Rev 1995;19:499–510.

[9] Barbas H, Blatt GJ. Topographically specific hippocampal projec-tions target functionally distinct prefrontal areas in the rhesus mon-key. Hippocampus 1995;5:511–33.

[10] Barbas H, Pandya DN. Architecture and intrinsic connectionsof the prefrontal cortex in the rhesus monkey. J Comp Neurol1989;286:353–75.

[11] Barbas H, Henion TH, Dermon CR. Diverse thalamic projectionsto the prefrontal cortex in the rhesus monkey. J Comp Neurol1991;313:65–94.

[12] Barbas H, Ghasghaei HT, Rempel-Clower NL, Xiao D. Anatomicbasis of functional specialization in prefrontal cortices in primates.In: Handbook of neuropsychology, vol. 7. Amsterdam: Elsevier;2002. p. 1–27.

[13] Baxter MG, Parker A, Lindner CCC, Izquierdo AD, Murray EA.Control of response selection by reinforcer value requires interactionof amygdala and orbitofrontal cortex. J Neurosci 2000;20:4311–9.

[14] Benton AL. The prefrontal region: its early history. In: Levin HS,Eisenberg HM, Benton AL, editors. Frontal lobe function and dys-function. New York: Oxford University Press; 1991. p. 3–32.

[15] Berendse HW, Groenewegen HJ. Restricted cortical terminal fields

of the midline and intralaminar thalamic nuclei in the rat. Neuro-science 1991;42:73–102.[16] Birrel JM, Brown VJ. Medial frontal cortex mediates perceputal

attentional set shifting in the rat. J Neurosci 2000;20:4320–4.[17] Brodmann K. Vergleichende Lokalisationslehre der Grosshirnhinde.

Barth: Leipzig. Lokalisationslehre der Grosshirnrinde. Leipzig:Barth-Verlag; 1909. p. 324.

[18] Broersen LM, Uylings HBM. Visual attention task performancein Wistar and Lister hooded rats: response inhibition deficits aftermedial prefrontal cortex lesions. Neuroscience 1999;94:47–57.

[19] Broersen LM, Heinsbroek RPW, de Bruin JPC, Uylings HBM,Olivier B. The role of the medial prefrontal cortex of rats inshort-term memory functioning: further support for involvementof cholinergic, rather than dopaminergic mechanisms. Brain Res1995a;674:221–9.

[20] Broersen LM, Heinsbroek RPW, de Bruin JPC, Laan JB, JoostenRNJMA, Olivier B. Local pharmacological manipulations of pre-frontal dopamine affect conflict behaviour in rats. Behav Pharmacol1995b;6:395–404.

[21] Brown VJ, Bowman EM. Rodent models of prefrontal corticalfunction. Trends Neurosci 2002;25:340–3.

[22] Butter CM, Snyder DR. Alterations in aversive and aggressivebehaviors following orbital frontal lesions in rhesus monkeys. ActaNeurobiol Exp 1972;32:115–56.

[23] Carmichael ST, Price JL. Architectonic subdivision of the orbitaland medial prefrontal cortex in the macaque monkey. J CompNeurol 1994;346:366–402.

[24] Carmichael ST, Price JL. Limbic connections of the orbital andmedial prefrontal cortex in macaque monkeys. J Comp Neurol1995;363:615–41.


12/15


[25] Carr DB, Sesack SR. Projections from the rat prefrontal cortex tothe ventral tegmental area: target specificity in the synaptic associ-ations with mesoaccumbens and mesocortical neurons. J Neurosci2000;20:3864–73.

[26] Cavada C, Goldman-Rakic PS. Posterior parietal cortex in rhesusmonkey. II. Evidence for segregated corticocortical networks linkingsensory and limbic areas with the frontal lobe. J Comp Neurol1989;287:422–45.

[27] Cavada C, Company T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-SuárezF. The anatomical connections of the macaque monkey orbitofrontalcortex. A review. Cereb Cortex 2000;10:220–42.

[28] Condé F, Audinat E, Maire-Lepoivre E, Crépel F. Afferent con-nections of the medial frontal cortex of the rat. A study using ret-rograde transport of fluorescent dyes. I. Thalamic Afferents. BrainRes Bull 1990;24:341–54.

[29] Condé F, Maire-Lepoivre E, Audinat E, Crépel F. Afferent con-nections of the medial frontal cortex of the rat. II. Cortical andsubcortical afferent. J Comp Neurol 1995;352:567–93.

[30] Corwin JV, Fussinger M, Meyer RC, King VR, Reep RL. Bilat-eral destruction of the ventrolateral orbital cortex produces allo-centric but not egocentric spatial deficits in rats. Behav Brain Res1994;61:79–86.

[31] Damasio AR. Descartes’ error: emotion, reason, and the humanbrain. New York: Grosset/Putnam; 1994. p. 312.

[32] De Bruin JPC. Social behavior and the prefrontal cortex. In: UylingsHBM, Van Eden CG, De Bruin JPC, Feenstra MPG, editors. Theprefrontal cortex: its structure, function and pathology. Progressin brain research, vol. 85. Amsterdam: Elsevier; 1990. p. 485–96.

[33] De Bruin JPC, Feenstra MPG, Broersen LM, Van Leeuwen M,Arens C, De Vries S, et al. Role of the prefrontal cortex of the rat inlearning and decision making: effects of transient inactivation. In:Uylings HBM, Van Eden CG, De Bruin JPC, Feenstra MGP, Pen-nartz CMA, editors. Cognition, emotion and autonomic responses:the integrative role of the prefrontal cortex and limbic structures.Progress in brain research, vol. 126. Amsterdam: Elsevier; 2000.p. 103–13.

[34] DeCoteau WE, Kesner RP, Williams JM. Short-term memory forfood reward magnitude: the role of the prefrontal cortex. BehavBrain Res 1997;88:239–49.

[35] Dermon CR, Barbas H. Contralateral thalamic projections predom-inantly reach transitional cortices in the rhesus monkey. J CompNeurol 1994;344:508–31.

[36] Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cin-gulate cortex to behavior. Brain 1995;118:279–306.

[37] Dinopoulos A, Karamanlidis AN, Papadopoulos G, AntonopoulosJ, Michaloudi H. Thalamic projections to motor, prefrontal and so-matosensory cortex in the sheep studied by means of the horseradishperoxidase transport method. J Comp Neurol 1985;241:63–81.

[38] Divac I. Frontal lobe system and spatial reversal in the rat. Neu-ropsychologia 1971;9:171–83.

[39] Donoghue JP, Wise SP. The motor cortex of the rat: cytoarchitec-

ture and microstimulation mapping. J Comp Neurol 1982;212:76–88.[40] Dunnett SB. Role of the prefrontal cortex and striatal output

systems in short-term memory deficits associated with ageing,basal forebrain lesions, and cholinergic-rich grafts. Can J Psychol1990;44:210–32.

[41] Feenstra MGP, De Bruin JPC. Strategy switching and the rat pre-frontal cortex. In: Otani S, editor. Prefrontal cortex: from synapticplasticity to cognition. Dordrecht: Wolters-Kluwer; 2003, in press.

[42] Frysztak RJ, Neafsey EJ. The effect of medial frontal cortex lesionson cardiovascular conditioned emotional responses in the rat. BrainRes 1994;643:181–93.

[43] Frysztak RJ, Neafsey EJ. The effect of medial frontal cortex lesionson respiration, ‘freezing’, and ultrasonic vocalizations during con-ditioned emotional responses in rat. Cereb Cortex 1991;1:418–25.

[44] Fuster JM. The prefrontal cortex: anatomy, physiology, and neu-ropsychology of the frontal lobe, 3rd ed. New York: Raven Press;1997. p. 333.

[45] Fuster JM. Linkage at the top. Neuron 1998;21:1223–4.[46] Gallagher M, McMahan RW, Schoenbaum G. Orbitofrontal cortex

and representations of incentive value in associative learning. JNeurosci 1999;19:6610–4.

[47] Gaspar P, Stepniewska I, Kaas JH. Topography and collateralizationof the dopaminergic projections to motor and lateral prefrontalcortex in owl monkeys. J Comp Neurol 1992;325:1–21.

[48] Gaykema RPA, Van Weeghel R, Hersh LB, Luiten PGM. Prefrontalcortical projections to the cholinergic neurons in the basal forebrain.J Comp Neurol 1991;303:563–83.

[49] Ghashghaei HT, Barbas H. Neural interaction between the basalforebrain and functionally distinct prefrontal cortices in the rhesusmonkey. Neuroscience 2001;103:593–614.

[50] Giguere M, Goldman-Rakic PS. Mediodorsal nucleus areal, lam-inar, and tangential distribution of afferents and efferents in thefrontal lobe of rhesus monkeys. J Comp Neurol 1988;277:195–213.

[51] Gisquet-Verrier P, Winocur G, Delatour B. Functional dissociationbetween dorsal and ventral regions of the medial prefrontal cortexin rats. Psychobiology 2000;28:248–60.

[52] Goldman-Rakic PS. Circuitry of the primate prefrontal cortex andregulation of behavior by representational memory. In: Plum F, ed-itor. Handbook of physiology: the nervous system. Vol. 5. Higherfunctions of the brain, Part 1. Bethesda, MD: American Physiolog-ical Society; 1987. p. 373–417.

[53] Granon S, Poucet B. Involvement of the rat prefrontal cortex incognitive functions: a central role for the prelimbic area. Psychobi-ology 2000;28:229–37.

[54] Groenewegen HJ. Organization of the afferent connections of themediodorsal thalamic nucleus in the rat, related to mediodorsal–prefrontal topography. Neuroscience 1988;24:379–431.

[55] Groenewegen HJ, Berendse HW. The specificity of the non-specificmidline and intralaminar thalamic nuclei. Trends Neurosci1994;17:52–7.

[56] Groenewegen HJ, Witter MP. Thalamus. In: Paxinos G, editor. Therat nervous system, 3rd ed. San Diego, CA: Academic Press; 2004.p. 407–453.

[57] Groenewegen HJ, Wright CI, Uylings HBM. The anatomical re-lationships of the prefrontal cortex with limbic structures and thebasal ganglia. J Psychopharmacol 1997;11:99–106.

[58] Groenewegen HJ, Berendse HW, Wolters JG, Lohman AHM. Theanatomical relationship of the prefrontal cortex with the striatopal-lidal system, the thalamus and the amygdala: evidence for a paral-lel organization. In: Uylings HBM, Van Eden CG, De Bruin JPC,Feenstra MPG, editors. The prefrontal cortex: its structure, func-tion and pathology. Progress in brain research, vol. 85. Amsterdam:Elsevier; 1990. p. 95–118.

[59] Guandalini P. The efferent connections to the thalamus and brain-stem of the physiologically defined eye field in the rat medial frontal

cortex. Brain Res Bull 2001;54:175–86.[60] Hajos M, Richards CD, Szekely AD, Sharp T. An electrophysio-logical and neuroanatomical study of the medial prefrontal corticalprojection to the midbrain raphe nuclei in the rat. Neuroscience1998;87:95–108.

[60a] Heidbreder CA, Groenewegen HJ. The medical prefrontal cortexin the rat: evidence for a dorso-ventral distinction based uponfunctional and anatomical characteristics. Neurosci. Biobehav. Rev.2003, in press.

[61] Iwaniuk A, Whishaw IQ. On the origin of skilled forelimb move-ments. Trends Neurosci 2000;23:372–6.

[62] Jay T, Witter MP. Distribution of hippocampal CA1 and subicularefferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris leucoagglutinin. J CompNeurol 1991;313:574–86.


13/15


[63] Jodo E, Aston-Jones G. Activation of locus coeruleus by prefrontalcortex is mediated by excitatory amino acid inputs. Brain Res1997;768:327–32.

[64] Jodo E, Chiang C, Aston-Jones G. Potent excitatory influence of prefrontal cortex on noradrenergic locus coeruleus neurons. Neuro-science 1998;83:63–79.

[65] Jones EG. Thalamus. New York: Plenum Press; 1985. p. 935.[66] Jones EG. A description of the human thalamus. In: Steriade M,

Jones EG, McCormick DA, editors. Thalamus, vol. 2. Amsterdam:Elsevier; 1997. p. 425–99.

[67] Jones EG, Leavitt RY. Retrograde axonal transport and the demon-stration of non-specific projections to the cerebral cortex and stria-tum from thalamic intralaminar nuclei in the rat. J Comp Neurol1974;154:349–78.

[68] Kaas JH. The organization of neocortex in mammals: implicationsfor theories of brain function. Ann Rev Psychol 1987;38:129–51.

[69] Kalsbeek A, Buijs RM, Hofman MA, Matthijssen MAH, Pool CW,Uylings HBM. Effects of neonatal thermal lesioning of mesocorticaldopaminergic projection on the development of the rat prefrontalcortex. Dev Brain Res 1987;32:123–32.

[70] Kesner RP. Subregional analysis of mnemonic functions of theprefrontal cortex in the rat. Psychobiology 2000;28:219–28.

[71] Kesner RP, Holbrook T. Dissociation of item and order spatialmemory in rats following medial prefrontal cortex lesions. Neu-ropsychologia 1987;25:653–64.

[72] Kievit J, Kuypers HGJM. Organization of the thalamo-cortical con-nexions to the frontal lobe in the rhesus monkey. Exp Brain Res1977;29:299–322.

[73] King V, Corwin JV. Neglect following unilateral ablation of thecaudal but not the rostral portion of medial agranular cortex of therat and the therapeutic effect of apomorphine. Behav Brain Res1990;37:169–84.

[74] Kolb B. Dissociation of the effects of lesions of the orbital ormedial aspect of the prefrontal cortex of the rat with respect toactivity. Behav Biol 1974a;10:329–43.

[75] Kolb B. Prefrontal lesions alter eating and hoarding behavior inrats. Physiol Behav 1974b;12:507–11.

[76] Kolb B. Some tests of response habituation in rats with prefrontallesions. Can J Psychol 1974c;28:260–7.[77] Kolb B. The social behavior of rats with chronic prefrontal lesions.

J Comp Physiol Psychol 1974d;87:466–74.[78] Kolb B. Functions of the frontal cortex of the rat: a comparative

review. Brain Res Rev 1984;8:65–98.[79] Kolb B. Animal models for human PFC-related disorders. In:

Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, Feen-stra MPG, editors. The prefrontal cortex: its structure, function andpathology. Progress in brain research, vol. 85. Amsterdam: Elsevier;1990. p. 501–19.

[80] Kolb B, Whishaw IQ. Dissociation of the contributions of theprefrontal, motor and parietal cortex to the control of movement inthe rat. Can J Psychol 1983a;37:211–32.

[81] Kolb B, Whishaw IQ. Generalizing in neuropsychology: problems

and principles underlying cross-species comparisons. In: RobinsonTE, editor. Behavioral contributions to brain research. New York:Oxford University Press; 1983b. p. 237–64.

[82] Kolb B, Whishaw IQ. Neonatal frontal lesions in the rat: sparingof learned but not species-typical behavior in the presence of re-duced brain weight and cortical thickness. J Comp Physiol Psychol1981;95:863–79.

[83] Kolb B, Whishaw IQ. Brain plasticity and behavior. Ann RevPsychol 1998;49:43–64.

[84] Kolb B, Whishaw IQ. Fundamentals of human neuropsychology,5th ed. New York: Worth; 2003.

[85] Kolb B, Buhrmann K, MacDonald R, Sutherland RJ. Dissociationof the medial prefrontal, posterior parietal, and posterior temporalcortex for spatial navigation and recognition memory in the rat.Cereb Cortex 1994;4:15–34.

[86] Kolb B, Nonneman AJ, Singh R. Double dissociation of spatialimpairment and perseveration following selective prefrontal lesionsin the rat. J Comp Physiol Psychol 1974;87:772–80.

[87] Krettek JE, Price JL. The cortical projections of the mediodorsalnucleus and adjacent thalamic nuclei in the rat. J Comp Neurol1977;171:157–91.

[88] Leonard CM. The prefrontal cortex of the rat. I. Cortical projectionof the mediodorsal nucleus. II. Efferent connections. Brain Res1969;12:321–43.

[89] Lewis DA, Sesack SR. Dopamine systems in the primate brain. In:Björklund A, Hökfelt T, Bloom FE, editors. Handbook of chem-ical neuroanatomy, Vol. 13. The primate nervous system, Part I.Amsterdam: Elsevier; 1997. p. 363–75.

[90] Lopez-Bendito G, Molnár Z. Thalamocortical development: howare we going to get there? Nat Rev Neurosci 2003;4:276–89.

[91] Loughlin SE, Fallon JH. Substantia nigra and ventral tegmental areaprojection to cortex: topography and collateralization. Neuroscience1984;11:425–35.

[92] Markow-Rajkowska G, Kosmal A. Organization of cortical affer-ents to the frontal association cortex in dogs. Acta Neurobiol Exp1987;47:137–61.

[93] McDonald AJ. Organization of amygdaloid projections to the pre-frontal cortex and associated striatum in the rat. Neuroscience1991;44:1–14.

[94] McFarland NR, Haber SN. Thalamic relay nuclei of the basalganglia form both reciprocal and nonreciprocal cortical connections,linking multiple frontal cortical areas. J Neurosci 2002;22:8117–32.

[95] Mesulam M-M. Spatial attention and neglect: parietal, frontal andcingulate contributions to the mental representation and attentionaltargeting of salient extrapersonal events. Philos Trans R Soc LondB: Biol Sci 1999;354:1325–46.

[96] Middleton FA, Strick PL. The temporal lobe is a target of outputfrom the basal ganglia. Proc Natl Acad Sci USA 1996;93:8683–7.

[97] Middleton FA, Strick PL. Basal-ganglia ‘projections’ to the pre-frontal cortex of the primate. Cereb Cortex 2000;12:926–35.

[98] Middleton FA, Strick PL. A revised neuroanatomy of frontal–subcortical circuits. In: Lichter DG, Cummings JL, editors. Frontal–

subcortical circuits in psychiatric and neurological disorders. NewYork: Guildford Press; 2001. p. 44–58.[99] Miller EK, Wallis JD. The prefrontal cortex and executive brain

functions. In: Squire LR, Bloom FE, Landis SC, Roberts JL, Zig-mond MJ, editors. Fundamental of neuroscience. San Diego, CA:Academic Press, Elsevier; 2003. p. 1353–76.

[100] Morán AM, Reinoso-Suárez F. Topographical organization of thethalamic afferent connections to the motor cortex in the cat. J CompNeurol 1988;270:64–85.

[101] Morgan MA, Schulkin J, LeDoux JE. Ventral medial prefrontalcortex and emotional perseveration: the memory for prior extinctiontraining. Behav Brain Res 2003, in press.

[102] Muir JL, Everitt BJ, Robbins TW. The cerebral cortex of the ratand visual attentional function: dissociable effects of mediofrontal,cingulate, anterior dorsolateral and parietal cortex lesions on a

five-choice serial reaction time task. Cereb Cortex 1996;6:470–81.[103] Nauta WJH. Neural associations of the amygdaloid complex in themonkey. Brain 1962;85:505–20.

[104] Neafsey EJ, Hurley-Gius KM, Arvanitis D. The topographical orga-nization of neurons in the rat medial frontal, insular and olfactorycortex to the solitary tract nucleus, olfactory bulb, periaqueductalgray and superior colliculus. Brain Res 1986;377:261–70.

[105] Northcutt RG, Kaas JH. The emergence and evolution of mammalianneocortex. Trends Neurosci 1995;18:373–9.

[106] Öngür D, Price JL. The organization of networks within the orbitaland medial prefrontal cortex of rats. Cereb Cortex 2000;10:206–19.

[107] Otto T, Eichenbaum H. Complementary roles of the orbitalprefrontal cortex and the perirhinal–entorhinal cortices in anodor-guided delayed-nonmatching-to-sample task. Behav Neurosci1992;106:762–75.


14/15


[108] Pandya DN, Yeterian EH. Prefrontal cortex in relation to othercortical areas in rhesus monkey: architecture and connections. In:Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, FeenstraMPG, editors. The prefrontal cortex: its structure, function andpathology. Progress in brain research, vol. 85. Amsterdam: Elsevier;1990. p. 63–94.

[109] Passingham R. The frontal lobes and voluntary action. Oxfordpsychology series, vol. 21. Oxford: Oxford University Press; 1993.p. 299.

[110] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. SanDiego, CA: Academic Press; 1998.

[111] Preuss TM. Do rats have a prefrontal cortex? The Rose–Woolsey–Akert program reconsidered. J Cogn Neurosci 1995;7:1–24.

[112] Preuss TM. Taking the measure of diversity: comparative alterna-tives to the model–animal paradigm in cortical neuroscience. BrainBehav Evol 2000;55:287–99.

[113] Preuss TM, Goldman-Rakic PS. Connections of the ventral gran-ular frontal cortex of macaques with perisylvian premotor and so-matosensory areas: anatomical evidence for somatic representationin primate frontal association cortex. J Comp Neurol 1989;282:293–316.

[114] Preuss TM, Kaas JH. Human brain evolution. In: Zigmond MJ,Bloom FE, Landis SC, Roberts JL, Squire LR, editors. Funda-mental of neuroscience. San Diego, CA: Academic Press; 1999.p. 1283–311.

[115] Pribram KH, Wilson WA, Connors J. Effects of lesions of themedial forebrain on alternation behavior of rhesus monkeys. ExpNeurol 1962;6:36–47.

[116] Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedialprefrontal cortex in the recovery of extinguished fear. J Neurosci2000;20:6225–31.

[117] Ragozzino ME, Kesner RP. The role of the agranular insular cortexin working memory for food reward value and allocentric space inrats. Behav Brain Res 1999;98:103–12.

[118] Ragozzino ME. The contribution of cholinergic and dopaminergicafferents in the rat prefrontal cortex to learning, memory, andattention. Psychobiology 2000;28:238–47.

[119] Rajkowska G, Kosmal A. Intrinsic connections and cytoarchitectonicdata of the frontal association cortex in the dog. Acta NeurobiolExp 48:169–92.

[120] Ramus SJ, Eichenbaum H. Neural correlates of olfactory recognitionmemory in the rat orbitofrontal cortex. J Neurosci 2000;20:8199–208.

[121] Ray JP, Price JL. The organization of the thalamocortical connec-tions of the mediodorsal thalamic nucleus in the rat, related tothe ventral forebrain–prefrontal cortex topography. J Comp Neurol1992;323:167–97.

[122] Ray JP, Price JL. The organization of projections from the mediodor-sal nucleus of the thalamus to orbital and medial prefrontal cortexin macaque monkeys. J Comp Neurol 1993;337:1–31.

[123] Reep RL, Corwin JV, King VR. Neural connections of orbital cortexin rats: topography of cortical and thalamic afferents. Exp Brain

Res 1996;111:215–32.[124] Reep RL, Corwin JV. Topographic organization of the striatal andthalamic connections of rat medial agranular cortex. Brain Res1999;841:43–52.

[125] Rolls ET. The functions of the orbitofrontal cortex. In: Stuss DT,Knight RT, editors. Principles of frontal lobe function. New York:Oxford University Press; 2002. p. 354–75.

[126] Rose JE, Woolsey CN. The orbitofrontal cortex and its connectionswith the mediodorsal nucleus in rabbit, sheep and cat. Res PublAssoc Nerv Ment Dis 1948;27:210–32.

[127] Russchen FT, Amaral DG, Price JL. The afferent connections of thesubstantia innominata in the monkey. J Comp Neurol 1985;242:1–27.

[128] Saddoris MP, Setlow B, Nugent S, Schoenbaum G. A reexaminationof the role of orbitofrontal cortex and basolateral amygdala in

acquisition and reversal of odor-guided go, no go discriminationtask. Soc Neurosci Abstr 2000;23.

[129] Sawaguchi T, Goldman-Rakic PS. The role of D1-dopamine receptorin working memory: local injections of dopamine antagonists intothe prefrontal cortex of rhesus monkeys performing an oculomotordelayed-response task. J Neurophysiol 1994;71:515–28.

[130] Schoenbaum G, Setlow B. Integrating orbitofrontal cortex into pre-frontal theory: common processing themes across species and sub-divisions. Learn Mem 2002;8:134–47.

[131] Schoenbaum G, Chiba AA, Gallagher M. Changes in functionalconnectivity in orbitofrontal cortex and basolateral amygdala duringlearning and reversal training. J Neurosci 2000;20:5179–89.

[132] Sherman SM, Guillery RW. Exploring the thalamus. San Diego,CA: Academic Press; 2001. p. 312.

[133] Shibata H. Topographic organization of subcortical projections to theanterior thalamic nuclei in the rat. J Comp Neurol 1992;323:117–27.

[134] Shipley JE, Kolb B. Neural correlates of species typical behavior inthe Syrian Golden hamster. J Comp Physiol Psychol 1977;91:1056–73.

[135] Stepniewska I, Kosmal A. Distribution of mediodorsal thalamicnucleus afferents originating in the prefrontal association cortex of the dog. Acta Neurobiol Exp 1986;46:311–22.

[136] Stepniewska I, Kosmal A. Differential projection from the motorand limbic cortical regions to the mediodorsal thalmic nucleus inthe dog. Acta Neurobiol Exp 1989;49:23–37.

[137] Swanson LW. Brain maps: structure of the rat brain. Amsterdam:Elsevier; 1992. p. 240.

[138] Uylings HBM, Van Eden CG. Qualitative and quantitative com-parison of the prefrontal cortex in rat and in primates, includinghumans. In: Uylings HBM, Van Eden CG, De Bruin JPC, CornerMA, Feenstra MPG, editors. The prefrontal cortex: its structure,function and pathology. Progress in brain research, vol. 85. Ams-terdam: Elsevier; 1990. p. 31–62.

[139] Uylings HBM. About assumptions in estimation of density of neu-rons and glial cells. Biol Psychiat 2002;51:840–2.

[140] Van Eden CG. Development of connections between the mediodor-

sal nucleus of the thalamus and the prefrontal cortex in the rat. JComp Neurol 1986;244:349–59.[141] Van Eden CG, Uylings HBM. Ctyoarchitectonic development of

the prefronal cortex of the rat. J Comp Neurol 1885;241:253–67.[142] Van Eden CG, Lamme VAF, Uylings HBM. Heterotopic cortical

afferents to the medial prefrontal cortex in the rat. A combinedretrograde and anterograde tracer study. Eur J Neurosci 1992;4:77–97.

[143] Vertes RP. Analysis of projections from the medial prefrontal cortexto the thalamus in the rat, with emphasis on nucleus reuniens. JComp Neurol 2002;442:163–87.

[144] Verwer RW, Van Vulpen EH, Van Uum JF. Postnatal develop-ment of amygdaloid projections to the prefrontal cortex in the ratstudied with retrograde and anterograde tracers. J Comp Neurol1996;376:75–96.

[145] Verwer RWH, Meijer RJ, Van Uum HFM, Witter MP. Collateralprojections from the rat hippocampal formation to the lateral andmedial prefrontal cortex. Hippocampus 1997;7:397–402.

[146] Warren JM, Kolb B. Generalizations in neuropsychology. In: FingerS, editor. Brain damage, behavior and the concept of recovery of function. New York: Plenum Press; 1978.

[147] Whishaw IQ. Change in sensory control related to behavioural andanatomical evolution of primate skilled reaching. Behav Brain Res,in press.

[148] Whishaw IQ, Pellis SM, Gorny BP. Skilled reaching in rats andhumans: evidence of parallel development or homology. BehavBrain Res 1992;47:59–70.

[149] Whishaw IQ, Pellis SM, Gorny BP. Medial frontal cortex lesionsimpair the aiming component of rat reaching. Behav Brain Res1992;50:93–104.


15/15


[150] Whishaw IQ, Tomie J, Kolb B. Ventrolateral frontal cortex lesionsin rats impair the acquisition and retention of a tactile–olfactoryconfigural task. Behav Neurosci 1992;106:597–603.

[151] Wikmark RGE, Divac I, Weiss R. Retention of spatial delayedalternation in rats with lesions of the frontal lobes: implicationsfor a comparative neuropsychology of the prefrontal system. BrainBehav Evol 1973;8:329–39.

[152] Williams SM, Goldman-Rakic PS. Widespread origin of the primatemesofrontal dopamine system. Cereb Cortex 1998;8:321–45.

[153] Woolsey CN. Organization of somatic sensory and motor areas of the cerebral cortex. In: Harlow HF, Woolsey CN, editors. Biologicaland biochemical bases of behavior. Madison, WI: University of Wisconsin Press; 1957.

[154] Wouterlood FG, Steinbusch HW, Luiten PG, Bol JG. Projec-tion from the prefrontal cortex to histaminergic cell groups inthe posterior hypothalamic region of the rat. Anterograde trac-ing with Phaseolus vulgaris leucoagglutinin ombined with im-munocytochemistry of histidine decarboxylase. Brain Res 1987;406:330–6.

[155] Yoshida A, Dostrovsky JO, Chiang CY. The afferent and efferentconnections of the nucleus submedius in the rat. J Comp Neurol1992;324:115–33.

[156] Zaborsky L, Gaykema RPA, Swanson DJ, Culliman WE. Corticalinput to the basal forebrain. Neuroscience 1997;79:1051–78.

[157] Zilles K. The cortex of the rat. A stereotaxic atlas. Berlin:Springer-Verlag; 1985. p. 121.

Documents

Do Rats Have a Prefrontal Cortex