Review

The medial prefrontal cortex in the rat: evidence for a dorso-ventral

distinction based upon functional and anatomical characteristics

Christian A. Heidbredera,*, Henk J. Groenewegenb

aDepartment of Biology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, Via A. Fleming 4, 37135 Verona, ItalybDepartment of Anatomy, Vrije Universiteit medical center (VUmc), Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands

Received 18 December 2002; revised 18 August 2003; accepted 4 September 2003

Abstract

The prefrontal cortex in rats can be distinguished anatomically from other frontal cortical areas both in terms of cytoarchitectonic

characteristics and neural connectivity, and it can be further subdivided into subterritories on the basis of such criteria. Functionally, the

prefrontal cortex of rats has been implicated in working memory, attention, response initiation and management of autonomic control and

emotion. In humans, dysfunction of prefrontal cortical areas with which the medial prefrontal cortex of the rat is most likely comparable is

related to psychopathology including schizophrenia, sociopathy, obsessive-compulsive disorder, depression, and drug abuse. Recent

literature points to the relevance of conducting a functional analysis of prefrontal subregions and supports the idea that the area of the medial

prefrontal cortex in rats is characterized by its own functional heterogeneity, which may be related to neuroanatomical and neurochemical

dissociations. The present review covers recent findings with the intent of correlating these distinct functional differences in the dorso-ventral

axis of the rat medial prefrontal cortex with anatomical and neurochemical patterns.

q 2003 Elsevier Ltd. All rights reserved.

Keywords: Medial prefrontal cortex; Anterior cingulate cortex; Prelimbic cortex; Infralimbic cortex; Dopamine; Norepinephrine; Serotonin; Acetylcholine

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556

2. Are there functional grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat? . . . 557

2.1. Selective lesions of the anterior cingulate/dorsal prelimbic cortices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557

2.2. Selective lesions of the ventral prelimbic/infralimbic cortices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557

2.3. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon behavioral characteristics . 561

3. Are there anatomical grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat? . . 562

3.1. Cortico-cortical connections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

3.1.1. Efferent connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

3.1.2. Afferent connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

3.2. Connections with basal forebrain, olfactory and limbic structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

3.3. Connections with basal ganglia structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

3.4. Connections with dopaminergic cell groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.5. Thalamo-cortico-thalamic relationships. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

3.6. Hypothalamic connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

3.7. Brain stem connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

3.8. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon neuroanatomical

characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

4. Are there neurochemical/histochemical grounds for a dissociation between subterritories of the medial prefrontal

cortex in the rat? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

4.1. Neurochemistry studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

4.1.1. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/j.neubiorev.2003.09.003

Neuroscience and Biobehavioral Reviews 27 (2003) 555–579

www.elsevier.com/locate/neubiorev

* Corresponding author. Tel.: þ39-45-921-9769; fax: þ39-45-921-8047.

E-mail address: christian_a_heidbreder@gsk.com (C.A. Heidbreder).

4.1.2. Serotonin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

4.1.3. Norepinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

4.1.4. Acetylcholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

4.2. Expression of immediate-early genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

4.3. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon neurochemical and

histochemical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574

1. Introduction

The mammalian prefrontal cortex has been classically

defined and delineated by anatomical criteria such as

cytoarchitectonic features (granular vs. agranular charac-

teristics) [15], connectivity with the mediodorsal thalamic

nucleus [1,6,71,73,76,105,111,161,168], input of dopamin-

ergic fibers from the ventral mesencephalon, or a combi-

nation of these criteria [7,13,48,49,196,200,211]. The rat

prefrontal cortex is, in general, tentatively divided into three

topologically different regions. First, a medially located

cortical region, the medial prefrontal cortex, which

constitutes the major portion of the medial wall of the

hemisphere anterior and dorsal to the genu of the corpus

callosum. Second, a ventrally located cortical region that is

termed the orbital prefrontal cortex and that lies in part

dorsal to the caudal end of the olfactory bulb in the dorsal

bank of the rhinal sulcus. Third, a laterally located cortical

region, the lateral or sulcal prefrontal cortex, which is also

referred to as the agranular insular cortex and, in rats, is

located in the anterior part of the rhinal sulcus [49,76,105,

111,112,172,173,183].

The medial prefrontal cortex will be the main focus of the

present review. This part of the prefrontal cortex in rats can

be further divided into at least four cytoarchitectonically

distinct areas: the medial precentral area (PrCm) or area Fr2,

the anterior cingulate area, the prelimbic area, and the

infralimbic area [105,203]. However, on the basis of several

anatomical criteria it has been suggested that there exists a

main subdivision of the medial prefrontal cortex into a dorsal

component, encompassing the FR2, dorsal anterior cingulate

areas, and the dorsal part of the prelimbic area, and a ventral

component that includes the ventral prelimbic, infralimbic

and medial orbital areas (Fig. 1) [11,74,191,220]. Such a

distinction between dorsal and ventral subdivisions might be

traced back to a phylogenetic origin and, most importantly in

the context of the present review, the literature appears to

provide ample indications for a concomitant functional–

behavioral differentiation of the medial prefrontal cortex into

dorsal and ventral parts.

As indicated above, in the context of the present account

it is important to realize that the prefrontal cortex evolved

from both an archicortical and paleocortical origin [142].

From the archicortical portion arose proisocortical areas 24

(anterior cingulate), 25 (infralimbic), and 32 (prelimbic),

which gave rise to both the dorsomedial and dorsolateral

prefrontal regions in primates. In fact, the prelimbic cortex

of rodents (especially rats) is the equivalent of Brodmann’s

area 32 in primates (especially macaques) [200]. In the

context of the developmental and evolutionary trends

recognized by Pandya and colleagues [6,142], it may be

stated that the infralimbic cortex forms the architectonically

Fig. 1. The cytoarchitecture of the medial prefrontal cortex is shown in six

coronal, Nissl stained sections through the frontal pole of the rat brain.

Boundaries of the different cytoarchitectonic fields are indicated with

arrowheads. The sections are equally spaced and approximately 0.5 mm

apart. The rostrocaudal level of the sections is also indicated in a

reconstruction of the medial view of the rostral part of the hemisphere

shown in Fig. 2. Abbreviations: ACd, dorsal anterior cingulate area; ACv,

ventral anterior cingulate area; FR2, frontal cortex area 2; IG, indusium

griseum; IL, infralimbic area; MO, medial orbital area; PL, prelimbic area;

TT, tenia tecta.

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579556

least developed prefrontal cortical area whereas there is a

trend towards further cytoarchitectonic differentiation, as

expressed by a clearer and more distinct segregation of

cortical layers in the prelimbic and the more dorsally located

anterior cingulate and Fr2 areas [105,106,203].

In the present review, we will first summarize a series of

studies demonstrating that the dorsal and ventral subregions

of the medial prefrontal cortex may be involved in different

behavioral functions or different aspects of the same

function. We will then hypothesize that such a functional

distinction is associated with differences not only in

cytoarchitectonics, but also in connectivity patterns, neuro-

chemistry and expression of immediate early genes. This

review will conclude with the suggestion that because of

chemo-anatomical differences in the dorso-ventral axis of

the rat medial prefrontal cortex, neurons originating from

deep layers of the prelimbic cortex may control a different

aspect of subcortical function compared with neurons

originating from the superficial layers of the anterior

cingulate cortex.

2. Are there functional grounds for a dissociationbetween subterritories of the medial prefrontal cortex

in the rat?

The medial prefrontal cortex as a whole has been

traditionally implicated in attentional processes, working

memory and behavioral flexibility. However, a growing body

of evidence is currently pointing towards the relevance of

conducting a functional analysis of medial prefrontal

subregions and supports the contention that the medial frontal

cortical wall is characterized by its own functional hetero-

geneity. In the following paragraphs we will review the recent

literature with the intent to demonstrate that such an analysis

supports a functional differentiation between the dorsal and

ventral subdivisions of the medial prefrontal cortex. The

thesis will be that the dorsal part of the medial prefrontal

cortex, including the dorsal anterior cingulate and dorsal

prelimbic cortices, is particularly involved in the temporal

shifting of behavioral sequences. Its ventral counterpart, that

includes the ventral prelimbic, infralimbic and medial orbital

cortices, appears to be specifically responsible for a flexible

shifting to new strategies related to spatial cues as well as, on

the basis of its connections with autonomic centers, for the

integration of internal physiological states with salient

environmental cues for the guidance of behavior.

2.1. Selective lesions of the anterior cingulate/dorsal

prelimbic cortices

Selective lesions of the anterior cingulate cortex can

increase conditioned fear responses [128], while they also

impair the acquisition of a four-way shuttle avoidance task

[63], and the performance in both a single-trial random-

foraging task and a delayed win-shift procedure [178]. Such

lesions further decrease the efficiency ratio in a sequential

task [126], block the expression of cocaine sensitization as

well as its concomitant increase in glutamate levels in the

core of the nucleus accumbens [151], and significantly

reduce cannabinoid receptor binding and G-protein acti-

vation [188]. Ibotenic acid lesions of the rostral part of the

anterior cingulate cortex, which corresponds to the peri-

genual Brodmann’s areas 24b, portions of perigenual 24a,

and caudodorsal area 32 have also been shown to reduce the

aversiveness or perceived unpleasantness of nociceptive

stimuli [99]. These effects are in contrast with lesions of the

caudal part of the anterior cingulate cortex, including

portions of postgenual Brodmann’s areas 24a and 24b, that

do not alter the affective processing of pain, but may rather

produce dysfunctions in the motor planning resulting from

nociceptor stimulation [99].

Lesions of the anterior cingulate cortex do not seem to

affect locomotor activity [63,198], performance in an eight-

arm radial maze [63], the development of sensitization to

either cocaine or amphetamine [197], the acquisition of

spatial learning [158], the switching from spatial to visual-

cued learning [158], the acquisition of visual-cued learning

[158], and the switching from visual-cued to spatial learning

[158]. In addition, the direct administration of scopolamine

into the anterior cingulate cortex does not affect working

memory for spatial locations [155], whereas the infusion of

acetylcholine into the anterior cingulate cortex decreases

blood pressure without altering heart rate [75]. Although

ibotenic acid lesions of the anterior cingulate cortex do not

affect the acquisition of conditional tasks such as a Go/No-

Go conditional discrimination task [40], these lesions seem

to selectively disrupt the temporal organization of beha-

vioral sequences regardless of the response’s characteristics

(e.g. slow vs. fast or right vs. left) [40]. Finally, quinolinic

acid lesions of the anterior cingulate and medial precentral

(FR2) cortices produce an impairment in memory for

egocentric responses, which may result from an inability to

remember what body turn was most recently made in a

delayed match-to-sample task that requires memory for a

908 right or left turn [156].

A summary of experimental lesions of the anterior

cingulate and dorsal prelimbic subregions of the medial

prefrontal cortex can be found in Table 1.

2.2. Selective lesions of the ventral prelimbic/infralimbic

cortices

Selective lesions of the ventral prelimbic/infralimbic

cortices increase resistance to extinction of conditioned fear

[129], enhance anxiety-related behaviors [87], increase

tachycardia to an excitatory conditioned stimulus [64].

Furthermore, they result in impairments of passive avoid-

ance [96], working memory [157], switching from spatial to

visual-cued learning and switching from visual-cued to

spatial learning in a cheeseboard task [158], cross-modal

shifts in a place-response learning in a cross-maze [159],

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 557

Table 1

Experimental manipulations of the anterior cingulate and dorsal prelimbic subregions of the rat medial prefrontal cortex; a selective summary of the recent

literature

Manipulation type Paradigm Experimental effect Reference

Mechanical lesion (microknife) Visual discrimination in rotating T-maze No effect in both the acquisition of visual

discrimination and the reversal learning task.

[113]

Deafferentation (unilateral

undercut lesion)

Density of cannabinoid receptor binding

with receptor-mediated G-protein

No effect [188]

Subpial suction Performance on a sequential task Decreased efficiency ratio (number of

reinforcements as percentage of number of bar

presses)

[126]

Decreased number of reinforcement during the

post-operative retention tests

Electrolytic lesion CER (Freezing) Acquisition: increased freezing response to both

context and CS þ tests

[128]

Extinction: increased amount of time to

extinguish freezing to both the context and

CS þ

Active Avoidance Decreased number of avoidance during testing

and increased number of trials to reach criterion

[63]

Locomotor activity No effect

8-Arm radial maze No effect

NMDA lesion Nonmatching-to-place task in the T-maze No effect [46]

Matching-to-place in the T-maze Impaired acquisition; increased perseveration by

nonmatching

Ibotenic acid lesion Expression of behavioral sensitization to

cocaine

Blockade of sensitization to the locomotor

activating effects of cocaine

[151]

Blockade of cocaine-induced changes in

glutamate release in the core of the nucleus

accumbens

Formalin test and CPP Rostral ACC: reduction in formalin-induced

aversion

[99]

Caudal ACC: no effect

Density of cannabinoid receptor binding

with receptor-mediated G-protein

60–70% decreased binding [188]

No effect on GTPgs binding

Go/No-go delayed conditioned discrimination

task

No effect when selection process does not

require temporal organization

[40]

Spatial delayed alternation task Impairment of acquisition of the task based on

temporal organization

Quinolinic acid lesion Development of behavioral sensitization to

cocaine

No effect [199]

Development of behavioral sensitization to

amphetamine

No effect [198]

Delayed match-to-sample task with memory

for a 908 right/left turn

Reduction in working memory performance for

egocentric responses

[156]

12-Arm radial maze Slight increase in the spatial locations tasks [157]

Electrical stimulation Gastric motility No effect [143]

Arterial blood pressure No effect [140,141]

Renal, superior mesenteric and iliac arterial

vascular conductance

c-FOS expression No effect

Lidocaine 2% Delayed spatial win-shift Increased number of across- phase errors

following pre-training injections

[178]

Increased number of across- phase errors

following pre-test injections

Random foraging Increased number of errors on lidocaine test days

Tetracaine 2% Spatial learning in the cheeseboard task Acquisition of spatial learning: no effect [158]

Switching from spatial to visual-cued learning:

no effect

Acquisition of visual-cued learning: no effect

Switching from visual-cued to spatial learning:

no effect

(continued on next page)

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579558

and reversal learning in a visual discrimination task [113].

Such lesions are also accompanied by an increase of the

number of errors when increasing delay in a delay non-

matching to position task [37–39], and of perseverative

responding in a five-choice reaction time task [144], while

they further impair learning if a fixed location has to be

reached from four different start positions in a navigation

task [39], block conditioned place preference to cocaine

[198], and attenuate the development of sensitization to

cocaine, but not amphetamine [197,199]. Tetrodotoxin-

induced inactivation of the prelimbic cortex was also shown

to block stress-induced reinstatement of drug seeking

behaviors in rats [21].

Although ibotenic acid lesions of the infralimbic cortex

fail to affect performance in the Morris water maze,

spontaneous and amphetamine-induced locomotor activity,

prepulse inhibition of the acoustic startle response and

consumption of sweetened milk [192], they can significantly

affect performance in the elevated plus maze and the taste

aversion test. Furthermore, these lesion effects are later-

alized to the right hemisphere [192]. These findings suggest

that the right infralimbic cortex is mainly involved in

behaviors specifically associated with anxiety or aversion.

NMDA-induced lesions of the prelimbic/infralimbic cortex

have also been shown to produce a significant increase in

perseveration that affects spatial memory performance [46].

This is especially striking in view of the failure to shift

response rules in matching-to-place tasks or on reversing

from matching- to nonmatching-to-place in the T-maze test

[46]. Additional studies [37,39] further suggest that

selective lesions of the ventral prelimbic/infralimbic sub-

region of the medial prefrontal cortex produce impairments

in the ability to adequately plan trajectories from different

start positions in a spatial navigation task. Finally, lesions of

the prelimbic/infralimbic cortex significantly disrupt

delayed response tasks further supporting the idea that the

prelimbic/infralimbic cortex is involved in behavioral

flexibility [35]. Interestingly, recent studies have elegantly

demonstrated that, in contrast with lesions of the anterior

cingulate cortex, bilateral excitotoxic lesions of the

prelimbic-infralimbic cortex can disrupt the information

processing involved in the preparation of rapid movement

triggered by a cue light [166]. These lesions not only altered

the motor readiness, that is the delay-dependent speeding of

the reaction time, but also the pattern of the premature

responses (impulsive responsiveness). Thus, these findings

suggest that the prelimbic/infralimbic cortex is also

implicated in the motor preparation of conditioned

responses, a feature that has been typically attributed to

the premotor and supplementary motor cortex in primates.

It is particularly striking that infralimbic neurons

recorded during fear conditioning and extinction fired to

the tone only when rats were recalling extinction on the

following day [125]. Specifically, rats that froze the least

showed the greatest increase in infralimbic tone responses.

Furthermore, conditioned tones paired with brief electrical

stimulation of the infralimbic cortex elicited low freezing in

rats that had not extinguished the response to the tone. Thus,

consolidation of extinction learning seems to potentiate

neuronal activity in the infralimbic cortex, which would

inhibit fear during subsequent encounters with fear-related

stimuli.

The electrical stimulation of the infralimbic cortex also

produces a significant decrease in gastric pressure, which is

reduced by atropine and completely abolished by vagotomy

[143]. Furthermore, the electrical stimulation of the

infralimbic and dorsal peduncular cortices produces

increases in vascular conductance (i.e. increases in blood

flow) in the renal, mesenteric, and iliac vascular beds [140].

In addition, microinjections of glutamate into the infra-

limbic, but not anterior cingulate cortex produce regional

haemodynamic responses that are qualitatively similar to

those produced by electrical stimulation [140]. These results

are supported by the existence of efferent pathways arising

from the ventral prelimbic/infralimbic cortex to central

antonomic loci such as the nucleus of the tractus solitarius,

rostral ventrolateral medulla and pariaqueductal gray matter

including connections with the lateral paragigantocellular

nucleus (see below). In fact, neurons from the lateral

paragigantocellular nucleus antidromically driven from the

infralimbic cortex are restricted to the ventral part of the

lateral paragigantocellular nucleus and spontaneously active

neurons from this nucleus can also show suppression of

activity following changes in blood pressure. It may also be

worth noting that recent experiments performed on male

CD-1 mice reported anxiolytic behavioral profiles in

Table 1 (continued)

Manipulation type Paradigm Experimental effect Reference

Scopolamine (1–10 mg) 12-Arm radial maze No effect on the working memory for spatial

locations

[155]

Acetylcholine (2.5–60 nmol) Blood pressure/heart rate Dose-dependent decrease in blood pressure

(reversal with either atropine (3 nmol) or 4-

DAMP (6.7 nmol)

[75]

No effect on heart rate

CS þ : reinforced conditioned stimulus; CER: conditioned emotional response; CPP: conditioned place preference. Rostral ACC: includes the perigenual

region (Brodmann’s area 24b, portions of perigenual 24a, and caudodorsal area 32 Caudal ACC: includes portions of postgenual Brodmann’s areas 24a and 24b.

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 559

Table 2

Experimental manipulations of the ventral prelimbic (PL) and/or infralimbic (IL) subregions of the rat medial prefrontal cortex; a selective summary of the

recent literature

Manipulation type Paradigm Experimental effect Reference

Mechanical lesion (microknife) Visual discrimination in rotating T-maze PL þ IL: no effect in the acquisition of visual

discrimination, but impairment in the reversal

learning task

[113]

Electrolytic lesion CER (freezing) Acquisition: no effect in both context and CS tests [128,129]

Extinction: increased amount of time to extinguish

freezing to the CS only

Active avoidance Increased number of avoidance during testing [63]

Passive avoidance Training (PL): increased latency to step down onto

the electrified grid

[96]

Test (PL): no effect

Training (IL): no effect

Test (IL): shorter latencies to step down onto the

electrified grid

Locomotor activity Increased activity [63]

Open field PL: decreased time spent in the center of the field [96]

IL: decreased time spent in the center of the field;

decreased ambulations (line crossings)

Exploration in a three-compartment CPP box PL: no effect

IL: no effect

Elevated plus maze PL þ IL: decreased time spent on the open arms; no

effect on the total number of crossings

8-Arm radial maze Increased number of arm entry errors [63]

NMDA lesion Respiratory rate (RSP), freezing, ultrasonic

vocalizations (USVs) during CER

Increased RSP to the CS þ [64]

Decreased amount of time spent freezing

Decreased USVs

Heart rate (HR) and blood pressure (BP) during CER BP: no effect to the CS þ [64]

HR: increased tachycardia to the CS þ

Nonmatching-to-place task in the T-maze PL þ IL: no effect [46]

Matching-to-place in the T-maze PL þ IL: impaired acquisition; general increase in

perseveration; deficit in reversing from matching to

nonmatching

Ibotenic acid lesion Delayed non-matching to position task (eight-arm

maze)

No effect on acquisition [37–39]

No effect on prospective planning of spatial

responses

No perseverative tendencies

Increased number of errors when increasing delay

from 10 to 40 sec

Navigation task No effect on learning simple goal-directed tasks [39]

Learning impairment if fixed location has to be

reached from four different start positions

Morris water maze test PL þ IL: no effect [192]

Spontaneous and amphetamine-induced activity PL þ IL: no effect

Elevated-plus-maze

Acoustic startle and prepulse inhibition PL þ IL (right hemisphere): anxiolytic effect;

increased time spent in open arms

Sweetened milk consumption PL þ IL: no effect

Taste aversion test PL þ IL: no effect

PL þ IL (right hemisphere): increased consumption

of sweetened milk þ quinine

Reaction time PL þ IL (bilateral): disruption of motor readiness

and altered pattern of premature responses

[102]

Expression of behavioral sensitization to cocaine No effect [151]

No change in glutamate release in the core of the

nucleus accumbens

Quinolinic acid lesion Development of behavioral sensitization to cocaine Blockade (locomotion and rearing, but not

grooming)

[197,199]

Development of behavioral sensitization to

amphetamine

No effect

(continued on next page)

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579560

the elevated plus-maze and enhanced implicit memory in

the Y-maze following the microinfusion of the selective

kappa1 opioid receptor agonist U-69,593 into the ventral

part of the medial prefrontal cortex [208]. These results

suggest that activation of kappa1 receptors in the ventral

prelimbic/infralimbic subregion of the medial prefrontal

cortex can blunt the incoming visceral information associ-

ated with the aversiveness of either maze.

A summary of experimental lesions of the ventral

prelimbic and/or infralimbic subregions of the medial

prefrontal cortex can be found in Table 2.

2.3. Towards a dorso-ventral distinction within the medial

prefrontal cortex based upon behavioral characteristics

The aforementioned findings suggest that although the

medial prefrontal cortex is clearly involved in a variety of

cognitive and emotional processes, its dorsal and ventral

subregions seem to be involved in different aspects of the

information processes. Thus, the dorsal part of the medial

prefrontal cortex (dorsal anterior cingulate and dorsal

prelimbic areas) is mainly involved in the temporal

patterning of behavioral sequences. In contrast, the ventral

Table 2 (continued)

Manipulation type Paradigm Experimental effect Reference

Development of CPP (cocaine, amphetamine,

morphine, MK801)

Blockade of cocaine CPP [198]

Five-choice reaction time task PL þ IL: decreased accuracy, incorrect latency,

omissions and increased perseverative responding

not reversible by the dopamine D2 antagonist

sulpiride

[144]

12-Arm radial maze Impairment of working memory for allocentric space [157]

Electrical stimulation Gastric motility IL: decrease in gastric pressure [143]

Arterial blood pressure IL þ DP: increased vascular conductance [140,141]

Renal, superior mesenteric and iliac arterial vascular

conductance

c-FOS expression IL þ DP: increased c-FOS expression

Lidocaine 2% Delayed spatial win-shift Increased number of both across- and within-phase

errors following pre-test injections

[178]

Random foraging No effect

Delayed spatial win-shift switched to random

foraging

Increased number of errors

Tetracaine 2% Spatial learning in the cheeseboard task Acquisition of spatial learning: No effect [158]

Switching from spatial to visual-cued learning:

increased search distance scores

Acquisition of visual-cued learning: no effect

Switching from visual-cued to spatial learning:

increased search distance scores on the first test

session only

Place-response learning in cross-maze Acquisition of place learning and shift to response

learning (cross-modal shift): Impairment (increased

trials to reach criterion)

[159]

Acquisition of response learning and shift to place

learning (cross-modal shift): Impairment (increased

trials to reach criterion)

Intramodal shift of the place discrimination: no

effect

Intramodal shift of the response discrimination: no

effect

Place learning when shift to a novel environment: no

effect

Response learning when shift to a novel

environment: no effect

Tetrodotoxin (TTX) Drug- and stress-triggered relapse to cocaine seeking PL: blockade of both drug- and stress-induced

reinstatement of cocaine seeking behavior

[21]

IL: no effect

Scopolamine (1–10 mg) 12-Arm radial maze Impairment of working memory for spatial locations

(5 and 10 mg) reversible by concomitant

administration of oxotremorine (2 mg)

[155]

Unless specified (see Refs. [96,113]), lesions included both the prelimbic and infralimbic subterritories of the medial prefrontal cortex. CS þ : reinforced

conditioned stimulus; CER: conditioned emotional response; CPP: conditioned place preference; DP: dorsal peduncular cortex; NMDA: N-methyl-D-

aspartate.

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 561

part of the medial prefrontal cortex (ventral prelimbic area,

as well as infralimbic and medial orbital cortices) appears to

be critical for the flexible shifting to new strategies or rules

in spatial or visual-cued discrimination tasks and, perhaps

even more importantly, for the integration of internal

physiological states with salient environmental cues to

guide behavior in situations of perceived threat or exposure

to aversive stimuli. The prelimbic/infralimbic cortex

appears to play also a key role in the preparatory processes

of reaction time performance. An additional prelimbic–

infralimbic dissociation has been recently described and

would suggest that the prelimbic cortex is responsible for

voluntary responses (goal-directed initial responding),

whereas the infralimbic cortex would mediate the progress-

ive and incremental ability of overtraining to lead to

behavioral autonomy and develop habits that are no longer

voluntary or goal-directed [102].

3. Are there anatomical grounds for a dissociation

between subterritories of the medial prefrontal

cortex in the rat?

As described in Section 1, the medial prefrontal cortex in

rats consists of several cytoarchitectonically distinct sub-

regions that, at least in part, can also be differentiated on the

basis of distinct afferent and efferent connectivity patterns

with cortical areas as well as with subcortical structures such

as the striatum, thalamus, amygdala, hypothalamus and

several brain stem nuclei [8,31,60,61,77,105,106,112,161,

183,200,205]. Although in most of these studies the

differential connectivity patterns within the medial prefrontal

cortex have been related to the various cytoarchitectonically

distinct areas, the results from several of the tracing studies

indicate that the distribution of anterogradely labeled fibers

or retrogradely labeled neurons does not in all cases strictly

adhere to cytoarchitectonically determined boundaries.

Thus, in both the dorso-ventral and rostro-caudal directions

particular afferents or efferents may show distributional

patterns that cut across cytoarchitectonic boundaries. Such

observations might indicate a functional differentiation of the

medial prefrontal cortex that, on the one hand, links together

certain cytoarchitectonic distinct areas and, on the other

hand, may ‘divide’ other areas into functionally different

subfields. A main trend that has been noticed is that the

patterns of connectivity of dorsally located, cytoarchitecto-

nically different areas share a number of similarities and that

these patterns are considerably different from those of

ventrally located medial prefrontal areas that again have a

number of characteristics in common.

In the following paragraphs we will provide a brief

overview of the afferent and efferent connectivity of the

medial prefrontal cortex. With respect to the efferent

connections of the medial prefrontal cortex, we will, in

part, refer to the patterns as observed in our own collec-

tion of experiments with anterograde tracers (Phaseolus

vulgaris-leucoagglutinin [PHA-L] and biotinylated dextran

amine [BDA]) in the medial wall of the frontal lobe.

For experimental details, we refer to previous publications

[11,216]. The results of multiple representative cases in

different parts of the medial prefrontal cortex are schema-

tically represented in Table 3. The location of the injection

sites of the cases documented in Table 3 is shown in Fig. 2.

In the descriptions below, emphasis will be placed on the

differences in connectivity between the dorsal and ventral

components of the medial prefrontal cortex. For further

details in the organization of the projections the reader is

referred to Table 3 and the original literature.

3.1. Cortico-cortical connections

There appears to be relatively strong interconnections

between ventrally as well as between dorsally located

cytoarchitectonic areas in the medial prefrontal cortex while

dorsoventral interconnections are rather limited. Further-

more, the dorsally located areas have stronger connections

with sensory and motor cortical cortices, while ventrally

located medial prefrontal areas have stronger relationships

with higher association and limbic cortices.

3.1.1. Efferent connections

The efferent projections of the infralimbic cortex are

directed rostrally and dorsally to the medial orbital and

prelimbic areas and, to a lesser degree, to the anterior

cingulate cortex [167]. In a lateral direction, infralimbic

fibers provide a strong innervation of the agranular

insular area, primarily its ventral subdivision, and a

moderately dense innervation of the piriform cortex and

the entorhinal area; fewer projections reach the perirhinal

cortex [92] (Table 3). Projections from the prelimbic area

have the tendency to reach more dorsal cortical areas

than those from the infralimbic area [167,183]. Within

the medial frontal wall, different parts of the prelimbic

cortex are interconnected via a strong intrinsic associ-

ation system [31] (Table 3). Prelimbic fibers also reach

the infralimbic cortex, the anterior cingulate and, to a

lesser degree, the premotor area FR2 and caudal

cingulate areas. In the lateral parts of the hemisphere,

prelimbic targets include the agranular insular area, most

prominently its dorsal subdivision (AId), and the more

caudal cortices around the rhinal sulcus, i.e. the posterior

agranular, perirhinal and entorhinal areas. There appear

to be clear differences between the dorsal and ventral

prelimbic areas in that only the ventral part of the

prelimbic cortex projects substantially to the piriform

cortex [33]. The more dorsally located parts of the

prelimbic area have slight projections to sensorimotor

areas in the frontal and parietal regions [183] (Table 3).

More substantial projections to the sensorimotor and

visual-related areas originate from the anterior cingulate

area and, in particular, frontal area FR2 [164,183].

The anterior cingulate area has its strongest projections

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579562

with more caudal parts of the cingulate area and the

retrosplenial cortex (Table 3).

3.1.2. Afferent connections

The distribution of cortical afferents of the medial

prefrontal cortex differs not only along the dorsoventral

coordinates but also in a rostrocaudal direction, ignoring to a

certain degree the boundaries between cytoarchitectonically

distinct cortical fields [31,205]. Thus, the ventromedial part

of the medial prefrontal cortex, encompassing the infra-

limbic and ventral prelimbic areas, receives cortical inputs

mainly from the perirhinal and ventral agranular insular

areas [162,205], as well as from the piriform cortex [33].

More dorsal parts of the prelimbic area, the anterior

cingulate and FR2 areas receive projections from secondary

visual, posterior agranular and retrosplenial cortices.

Rostral parts of the anterior cingulate and FR2 areas appear

to be mostly innervated by fronto-parietal motor and

somatosensory, as well as temporal association and

posterior agranular insular areas [31,163,164,205]. As

stressed by Conde et al. [31], specific cortico-cortical

projection patterns adhere only to a certain degree to the

different cytoarchitectonic fields. Thus, efferent and afferent

projection patterns of dorsally located prefrontal areas,

primarily characterized by somatosensory cortical associ-

ations, or more ventrally located prefrontal areas, predomi-

nantly characterized by cortical relationships with limbic

and associational areas, show gradual transitions rather than

sharp boundaries [31,183,205]. Moreover, cortical associ-

ation systems within the medial prefrontal cortex are

predominantly oriented in a horizontal direction, such that

particular areas within the medial prefrontal cortex are

connected primarily with more rostral or caudal parts of the

medial frontal wall rather than with more dorsally or

ventrally located cortical areas [31] (own unpublished

observations, see Table 3).

3.2. Connections with basal forebrain, olfactory

and limbic structures

Medial prefrontal cortex projections to septal and basal

forebrain regions, that include the cholinergic cell groups in

the medial septal nucleus and the vertical and horizontal

limbs of the diagonal band of Broca, are also topographi-

cally organized. Thus, more ventral regions, including the

infralimbic and ventral prelimbic areas, project more

densely to the septum and medial areas of the basal

forebrain, while the dorsal parts of the prelimbic area and

the anterior cingulate area project more laterally to reach the

horizontal limb of the diagonal band of Broca [66,67,183]

(Table 3). Non-cholinergic cell groups in the basal forebrain

are also reached by medial prefrontal fibers. There is a weak

to moderate innervation of lateral parts of the bed nucleus of

the stria terminalis complex originating in particular from

the ventral parts of the medial prefrontal cortex [92,183]

(Table 3). Olfactory structures like the anterior olfactory

nucleus, the piriform cortex and the superficial layers of the

olfactory tubercle are primarily reached by the infralimbic

and ventral parts of the prelimbic areas and far less from

more dorsal regions [11,33] (Table 3).

The horizontal limb of the diagonal band of Broca gives

rise to cholinergic projections to the medial prefrontal

cortex; ventral regions are innervated by medially located

neurons while more dorsal cortical regions receive inputs

from progressively more lateral neurons in this cholinergic

nucleus [169].

‘Core’ limbic structures like the hippocampus and

amygdala are predominantly connected with the ventrally

located medial prefrontal areas, although specific parts of

the amygdala also reach more dorsal areas. Prefrontal

relationships with the hippocampal formation (hippo-

campus proper and subiculum) are virtually unidirectional:

the prefrontal cortex receives inputs from the hippocampus

[23,65,95], but only very few medial prefrontal fibers have

been described to reach the hippocampal formation directly

[92,183] (Table 3). Indirect prefrontal influence on the

hippocampus, e.g. via the entorhinal area or subcortical

diencephalic structures, is of course possible. Hippocampal-

prefrontal projections, which are derived predominantly

from the subiculum and CA1 in the ventral part of the

hippocampal formation, distribute mainly to the infralimbic

and ventral prelimbic areas [95,193]. Connections between

the medial prefrontal cortex and the parahippocampal cortex

are bi-directional. Whereas the perirhinal cortex projects

predominantly to infralimbic and ventral prelimbic areas,

the dorsolateral entorhinal area reaches the entire medial

frontal wall [41,205]. Medial prefrontal projections to the

entorhinal cortex originate mostly from the infralimbic

cortex, while projections to the perirhinal cortex originate,

in addition, from more dorsally located areas [92,183]

(Table 3).

Although as a whole the amygdaloid complex is

connected with the entire medial prefrontal cortex, there

appears to be a clear predominance for interconnections

with the more ventrally located areas. The connections

between the prefrontal cortex and the amygdaloid complex

are reciprocal and more extensive than the hippocampal–

prefrontal connections. The infralimbic area projects

heavily to the (lateral capsular) central, medial, accessory

basal and cortical amygdaloid nuclei [92,122,123] (Table 3).

The ventral prelimbic area has a very similar distribution

pattern of its projections to the amygdaloid complex, while

more dorsal regions of the prelimbic area and the anterior

cingulate area reach only restricted regions of the basal and

lateral nuclei and, to a lesser degree the central nucleus

(Table 3). Frontal area Fr2 (or the medial precentral area)

sends fibers to even more restricted parts of the amygdala,

mainly involving the basal nucleus [122,123,139,183]

(Table 3).

Amygdaloid projections to the medial prefrontal cortex

arise predominantly from the caudal parts of the basal

amygdaloid complex and to a lesser degree from the lateral

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 563

Table 3

Patterns of efferent connections of the ventral prelimbic and infralimbic areas (A) and the dorsal prelimbic, dorsal anterior cingulate and FR2 areas (B)

A Infralimbic (IL) Ventral prelimbic (PLv)

93208 d 93272 d þ s 90045 d þ s 93172 d 93232 d þ s 93280 d þ s 89509 d

Cortical structures

Sensorimotor cx – – – – – – ,FR2 – – – , – – –

Visual cx – – – – – – ,Temporal cx – – , , – – – –

ACd – – , – † , †

ACv †† † † † † , ††

Retrosplenial cx † , , , , , ,PLd – † † – † † †

PLv † †† ††† †† ††† ††† †††

IL/MO † †† †† †† ††† ††† ††

Orbital cx , , †† – – , †

Sulcal PFC/AId – , , †† †† † ,Sulcal PFC/AIv †† †† † † † † ††

Sulcal PFC/AIp – † , , † † ,Perirhinal cx – † †† – † , ,Entorhinal cx † † †† – , , ,Hippocampus – – – – – – –

Basal forebrain, olfactory structures and amygdala

Septum lateral †† † † , , , ,Septum medial , † † , , , ,BNST medial – – † – – – ,BNST lateral , , † , † † †

DBB/horizontal limb †† † † † † † †

Amygdala/basal nuclei † † †† – † † ,Amygdala/lateral nuclei , – – – † , ,Amygdala/central nuclei † † †† – †† – †

Amydgala/medial nuclei , † † – † , †

Amygdala/cortical nuclei – , † – , – ,Sublenticular EA † † † , † † ,Anterior olfactory nucleus †† † †† † † , †

Taenia tecta † , † † † , †

Piriform cortex , – † – † , †

Endopiriform nucleus † †† †† , † † †

Claustrum †† † , † †† † †

Basal ganglia structures

Caudate–putamen/medial , † † †† †† †† †

Accumbens core/medial † † † † † †† †

Accumbens shell/medial †† †† ††† †† †† †† ††

Olfactory tubercle –striatal †† †† ††† , †† †† †

Olfactory tubercle –pallidal , – , – , , †

Ventral pallidum , , , – , , †

Subthalamic nucleus – , – – , , ,

Hypothalamus

Preoptic area medial , † † , †† † ,Preoptic area lateral † † † † † † †

Hypothalamus medial †† †† † – † – †

Hypothalamus lateral †† †† †† , †† †† ††

Mammillary region † †† †† † † † ,Zona Incerta , † † † , , †

Thalamus

Anterior nuclei † † †† †† † , ††

Parataenial nucleus ††† ††† ††† ††† †† ††† †††

Mediodorsal nucleus ††† ††† ††† ††† ††† ††† †††

Lateral dorsal nucleus , † , , , † †

Lateral posterior med † † , † † † †

Midline thalamic nuclei PV † †† † † † † ††

Midline thalamic nuclei Re †† †† †† † ††† †† †††

(continued on next page)

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579564

Table 3 (continued)

B Dorsal prelimbic (PLd) Dorsal anterior cingulate (Acd) þ FR2

89502 d 89590 s 89634 d 89474 d 90090 d þ s 90091 d þ s 89703 d þ s 90383 s 90328 d

Cortical structures

Sensorimotor cx † † † †† † † † , ††

FR2 † , † , † † †† †† ††

Visual cx † † † †† , † † , –

Temporal cx , , , , † † , , ,ACd †† †† †† †† †† ††† ††† †† ††

ACv † , † † , , † – –

Retrosplenial cx , – , † – † † † ,PLd ††† ††† ††† ††† † † †† – ,PLv † † †† †† , , , – –

IL/MO † , † † , – , – –

Orbital cx † , , † † †† †† † –

Sulcal PFC/Aid † † †† †† † , † – –

Sulcal PFC/Aiv † – † , – – – – –

Sulcal PFC/Aip † – † † – – – , –

Perirhinal cortex , – † † † † † † –

Entorhinal cx – – , , , – – – –

Hippocampus – – – – – – – – –

Basal forebrain, olfactory structures and amygdala

Septum lateral , † , , – , – – –

Septum medial – – , – – – – – –

BNST medial – – – – – – – – –

BNST lateral – – – – – – – – –

DBB – horizontal limb , † , , , – , , –

Amygdala/basal nuclei , †† †† † † †† † † –

Amygdala/lateral nucleus † – † , , , – , –

Amygdala/central nuclei – – – – – – – – –

Amydgala/medial nuclei – – , – – – – – –

Amygdala/cortical nuclei – – – – – – – – –

Sublenticular EA – – – – – – – – –

Anterior olfactory nucleus † – – † – , – – –

Taenia tecta , – , , – – – – –

Piriform cortex – – – – – – – – –

Endopiriform nu , – , , – – – – –

Claustrum † † †† †† † † †† † ,

Basal ganglia structures

Caudate–putamen intermediate/lateral ††† †† ††† †† ††† ††† ††† †† ††

Accumbens core/lateral †† †† †† † † † † † –

Accumbens shell/lateral , , , , † † – – –

Olfactory tubercle –striatal – , , – , , – – –

Olfactory tubercle –pallidal – – – – – – – – –

Ventral pallidum – – – – – – – – –

Subthalamic nucleus , , † † , , † † –

Hypothalamus

Preoptic area medial – , , – – – – – –

Preoptic area lateral – , , – † – , – –

Hypothalamus medial – – † , – – – – –

Hypothalamus lateral , , † , † – , , –

Mamillary region – – † – – – – – –

Zona Incerta , , † † † † †† † –

Thalamus

Anterior nuclei † † † † †† †† ††† – –

Parataenial nucleus † – † † – , , – –

Mediodorsal nucleus ††† †† ††† ††† ††† ††† †† † –

Lateral dorsal nucleus † † † † † † † † ††

Lateral posterior † † †† † † †† † , †

Midline thalamic nuclei PV , †† †† † , – – – –

Midline thalamic nuclei Re , †† † † †† †† † † –

(continued on next page)

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 565

amygdaloid nucleus and the periamygdaloid cortex [106,

120,121]. The projections from the basal amygdaloid

complex to the medial prefrontal cortex show a topogra-

phical arrangement [27]. The caudal parts of the parvicel-

lular basal nucleus project primarily to the deep layers of the

infralimbic and ventral prelimbic areas. The caudal part of

the accessory basal nucleus projects to a larger area of the

medial frontal wall, including predominantly the infralimbic

and prelimbic areas and, to a lesser degree, the anterior

cingulate and Fr2 areas [106,147] (Wright and Groenewe-

gen, unpublished observations). It is important to note that

specific parts of the basal amygdaloid complex project to

subareas in the medial prefrontal cortex and subregions in

the ventral striatum that are, in turn, associated with each

other by prefrontal corticostriatal projections [121,216].

3.3. Connections with basal ganglia structures

The rather strict topographical arrangement of projec-

tions from the prefrontal cortex to different parts of the basal

ganglia, in particular the striatum, is clearly in line with the

proposed dorso-ventral functional distinction with the

medial prefrontal cortex [8,11,117,183,216]. Thus, corti-

costriatal projections from area Fr2 reach a central part of

the caudate-putamen, a striatal region that is among others

associated with attentional mechanisms [28]. The projec-

tions from the anterior cingulate area terminate more

medially and extend further ventrally to include the core

of the nucleus accumbens. The dorsal part of the prelimbic

area projects to even more medial parts of the caudate-

putamen, bordering the wall of the lateral ventricle, the core

of the nucleus accumbens and, to a lesser degree, the rostral

pole of the nucleus accumbens [47]. The ventral part of the

prelimbic cortex sends fibers to the extreme ventromedial

parts of the caudate-putamen, the adjacent core of the

nucleus accumbens and, in addition, the dorsal and medial

parts of the shell and the medial part of the olfactory

tubercle [11,47,50]. The infralimbic and medial orbital

areas reach almost exclusively the medial shell of the

nucleus accumbens, but include also parts of the medial core

[11,47,92,183]. This brief survey indicates that only the

ventral prelimbic, infralimbic and medial orbital areas send

substantial projections to the shell of the nucleus accum-

bens, whereas more dorsal prefrontal regions project to the

core of this nucleus and the dorsally adjacent caudate-

putamen. Clearly, core and shell have been hypothesized to

be differentially involved in learning processes [22,45].

Via the cortico-striatal projections just described, the

various areas in the medial prefrontal cortex give origin to

different, largely parallel-organized basal ganglia—thala-

mocortical circuits. These circuits ‘feed back’ via various

thalamic relays to the medial prefrontal area from which the

circuit originates, leading to (partially) closed or ‘re-entrant’

circuits [78–80]. In addition, such circuits might form

indirect links between the different medial prefrontal

cortical areas, such that the more ventrally located

infralimbic and ventral prelimbic areas ‘feed forward’ via

the shell of the nucleus accumbens into ventral pallido-

thalamo-cortical pathways that reach more dorsally located

cortices like the dorsal prelimbic and anterior cingulate

areas [80,218,219].

A further complexity in the prefrontal cortico-striatal

systems arises from the fact that the laminar origin of

corticostriatal fibers is related to the striatal compartmental

organization. That is, the superficial layers of the

medial prefrontal cortex project predominantly to the matrix

compartment of both the caudate-putamen and the core of the

nucleus accumbens. In contrast, the deep layers of the medial

Table 3 (continued)

A Infralimbic (IL) Ventral prelimbic (PLv)

93208 d 93272 d þ s 90045 d þ s 93172 d 93232 d þ s 93280 d þ s 89509 d

Intralaminar nuclei – – – , † † †

Reticular thalamic nucleus † † † † † † †

Ventromedial nucleus – – – , † , ,Ventrolateral nucleus – – – – – – –

Lateral habenula (med) † † , – † , †

Brainstem

Superior colliculus – – – – – – ,Periaqueductal gray †† † † †† †† † †

Periventricular zone (rostral) †† †† † †† †† † †

VTA/substantia nigra †† †† † , †† † ††

Raphe nuclei , †† † , † † †

Interpeduncular nucleus , † † , , – ,Dorsolateral tegmental nu , † † – †† † †

Peribrachial nuclei , , † – † , †

Pedunculopontine tegmental region , – , – † † ,Pontine reticular formation † † † , † † †

Locus coeruleus , , † – † † ,

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579566

cortical areas provide rather specific inputs to the patch

compartment of caudate-putamen and the core of the

accumbens. A gradient also exists: the deep layers of the

more ventrally located infralimbic and prelimbic areas have

stronger inputs into the patch compartment than those of the

more dorsally located cortical areas of the medial frontal wall

[11,69]. In addition, the deep layers of the ventral part of the

prelimbic area project to specific regions in the medial shell

of the nucleus accumbens [11,47,50]. This specific organiz-

ation is of interest in view of the fact that the striatal patch

compartment, as well as the (medial) shell of the nucleus

accumbens have a direct input to the dopaminergic neurons

in the ventral tegmental area and the pars compacta of the

substantia nigra [12,68,70]. The ventral prefrontal areas thus

appear to have a rather strong influence on the mesencephalic

dopamine system via the ventral striatum. In addition, these

ventrally located areas have a stronger direct influence on

dopamine neurons than the more dorsal parts of the medial

prefrontal cortex (see below).

Whereas the projections from the medial prefrontal

cortex to the striatum are massive, weaker medial frontal

cortical projections reach the medial part of the subthalamic

nucleus [10,117]. The prelimbic area projects onto the most

medial part of the subthalamic nucleus, while the anterior

cingulate and FR2 areas project more laterally in

the nucleus. The infralimbic cortex does not project into

the subthalamic nucleus, but reaches the lateral hypothala-

mic area just medial to this nucleus [10,92] (Table 3). The

substantia nigra pars reticulata and (ventral) pallidal areas

contain only sporadic fibers following anterograde tracer

injections in the medial prefrontal cortex (Table 3).

3.4. Connections with dopaminergic cell groups

Whereas the entire medial prefrontal cortex is supplied

by dopaminergic fibers, the ventral areas are most densely

innervated [196]. This mesocortical dopaminergic inner-

vation arises primarily from the ventral tegmental area and

to a lesser degree from the substantia nigra pars compacta.

An inverted dorso-ventral topography between the medial

prefrontal cortex and the ventral tegmental area has been

observed: more dorsally located dopamine neurons in the

ventral tegmental area innervate the more ventral sites of the

medial prefrontal cortex, whereas more ventrally located

neurons in the ventral tegmental area project to the more

dorsal part of the medial prefrontal cortex [42].

Table 3 (continued)

B Dorsal prelimbic (PLd) Dorsal anterior cingulate (Acd) þ FR2

89502 d 89590 s 89634 d 89474 d 90090 d þ s 90091 d þ s 89703 d þ s 90383 s 90328 d

Intralaminar nuclei ††† † †† †† †† †† †† † ††

Reticular thalamic nucleus † † † † † † † , †

Ventromedial nucleus † † †† †† † †† †† † †

Ventrolateral nucleus † – – , , † † † ††

Lateral habenula , , † , , – – – –

Brainstem

Superior colliculus – † , , † †† † , –

Periaqueductal gray , † † † † † † † –

Periventricular zone (rostral) , † † †† † †† † † –

VTA/substantia nigra , † † † † † † , –

Raphe nuclei – † † , † † , , –

Interpeduncular nucleus , , – , – – – –

Dorsolateral tegmental nu – † , † † , – – –

Peribrachial nuclei – – – – , – – –

Pedunculopontine tegmental region , † † , † , – – –

Pontine reticular formation † † † † † † † † –

Locus coeruleus † † † , † , – – –

The relative density of fibers and terminals is represented from cases with anterograde tracer injections (PHA-L and BDA) in different parts of the medial

prefrontal cortex and the FR2 area. The location of the injection sites is represented in Fig. 2. The number of each experiment is followed by ‘d’ and/or ‘s’,

indicating the location of the injection site in deep (d) or superficial (s) cortical layers, respectively. The densities are represented as follows: –, no labeled

fibers; , , sporadic fibers; †, light projection; ††, moderate projection; †††, dense projection. A. Injection sites in the ventral part of the medial prefrontal

cortex (infralimbic, medial orbital and ventral prelimbic areas); B. injection sites in the doral part of the medial prefrontal cortex (dorsal prelimbic and dorsal

anterior cingulate areas) and area FR2. Note that injections in different regions may result in labeling in the same structures, but that there exist topographical

arrangements such that ventral regions project to a different part of a certain nucleus or cortical area than dorsal regions of the medial prefrontal cortex. This, for

example, holds for projections to the striatum, the mediodoral and anterior thalamic nuclei, and most of the cortical regions that are only globally indicated in

this table. For differences relevant to the present paper, details are given in the text; for further details of the fine topographical arrangements, we refer to the

original literature. Abbreviations: 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; BNST, bed nucleus of the stria terminalis; DBB, nucleus of diagonal band of Broca; EA, extended

amygdala; FR2, frontal cortex area 2; IL, infralimbic area; MO, medial orbital area; PLd, dorsal part of the prelimbic area; PLv, ventral part of the prelimbic

area; PV, paraventicular thalamic nucleus; Re, reuniens thalamic nucleus; VTA, ventral tegmental area.

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 567

Furthermore, there appears to exist a bilaminar distribution

of dopaminergic axons with a differential origin of these

fibers in the ventral mesencephalon. Thus, superficially

terminating dopaminergic fibers, predominantly targeting

the anterior cingulate area, are derived primarily from

neurons in the pars compacta of the substantia nigra (A9 cell

group). Dopaminergic axons targeting deeper layers, most

prominently in the ventrally located prelimbic and infra-

limbic areas, originate predominantly from the ventral

tegmental area (A10 cell group). Recent immunohisto-

chemical studies have demonstrated that the dopamine

transporter is relatively abundantly expressed on dopamin-

ergic fibers in the superficial layers of the anterior cingulate

area and that the immunoreactivity is distributed over both

the terminals and intervaricose segments of the axons. In

contrast, the dopamine transporter is much less abundant on

fibers in the deep layers of the prelimbic area and here they

are expressed primarily in the intervaricose segments of the

dopaminergic fibers [184]. These data support the differen-

tial origin of these dopaminergic fibers. They might also

imply that dopamine is differentially available in the dorsal

and ventral parts of the medial prefrontal cortex

(Section 4.1.1).

It is important to note that medial prefrontal fibers project

back to the ventral tegmental area and pars compacta of

the substantia nigra and, in this way, may have a direct

influence on dopaminergic neurons in the ventral mesence-

phalon [8,24,92,183]. Ventral areas in the medial prefrontal

cortical areas do project more densely to these dopamin-

ergic cell groups [182,183,194] (see also Table 3).

3.5. Thalamo-cortico-thalamic relationships

Reciprocal and topographically organized

connections between the medial prefrontal cortex and

different thalamic nuclei have been described in great detail

[57,58,76,92,105,161,183,206]. In brief, a ventral-to-dorsal

gradient in the medial prefrontal cortex globally maps onto a

medial-to-lateral gradient in the dorsal thalamus where the

medial prefrontal projections as a whole primarily involve

the midline, parataenial, anteromedial, mediodorsal and

intralaminar thalamic nuclei. The ventrally located infra-

limbic and ventral prelimbic areas reach primarily the

midline nuclei and the medial segment of the mediodorsal

nucleus, while the dorsal prelimbic area together with the

anterior cingulate and FR2 areas project to the lateral

segment of the mediodorsal nucleus and the intralaminar

nuclei [62,76,206] (Table 3). Strong projections from all

medial cortical areas reach the ventral thalamus, in

particular the nucleus reuniens, in which a cortical

topography is less apparent [206]. Sporadic projections are

found to the lateral dorsal and lateral posterior nuclei as well

as to the reticular and ventromedial thalamic nuclei

(Table 3).

The corticothalamic projections are to a large extent

reciprocated by thalamocortical fibers in a rather strict

topographical similarity. Whereas the corticothalamic

projections predominantly originate from the deepest

cortical layer VI, the reciprocal projections from the

mediodorsal nucleus are primarily directed to layer III.

The midline and intralaminar nuclei project to the deeper

layers V and VI of the medial prefrontal cortex, the midline

nuclei mostly to the infralimbic and ventral prelimbic areas,

the intralaminar nuclei to the more dorsally located cortical

areas in the medial wall. The midline nuclei are thought to

be primarily involved in arousal and visceral functions

while the intralaminar nuclei subserve orienting and

attentional aspects of behavior [107,201]. The ventromedial

thalamic nucleus has a wide distribution of fibers over

almost the entire frontal lobe and these projections reach the

most superficial layers [10,76,80,88].

3.6. Hypothalamic connections

Medial prefrontal projections to the hypothalamus

predominantly arise from the ventrally located cortical

areas [183] (Table 3). In rats, the orbital and agranular

insular prefrontal regions also contribute to these

projections. By way of hypothalamic projections, the

prefrontal cortex has an important influence on

behavioral and autonomic functions. In a recent paper

Floyd et al. [61] have elegantly shown the clear topography

Fig. 2. Medial view of the rostral part of the rat hemisphere with the

approximate locations of the injections of anterograde tracers (BDA and

PHA-L) in the medial prefrontal cortex. The levels of the sections shown in

Fig. 1 and the boundaries between the cytoarchitectonic areas are indicated.

The efferent projection patterns, resulting from the different injection sites,

are summarized in Table 3. Abbreviations: ac, anterior commissure; cc,

corpus callosum; ACd, dorsal anterior cingulate area; ACv, ventral anterior

cingulate area; FR2, frontal cortex area 2; IL, infralimbic area; MO, medial

orbital area; OB, olfactory bulb; PLd, dorsal part of the prelimbic area; PLv,

ventral part of the prelimbic area.

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579568

in the projections from different parts of the medial

prefrontal cortex to specific regions in the hypothalamus.

Thus, the dorsally located anterior cingulate areas have a

rather restricted projection field in the hypothalamus,

primarily including the posterior hypothalamus. In contrast,

the ventrally located prelimbic and infralimbic areas have a

much wider distribution within the hypothalamus including

the (dorso)medial and lateral hypothalamic areas throughout

the rostrocaudal extent of the hypothalamus. Caudal parts of

both the infralimbic and prelimbic areas reach primarily

dorsal and medial hypothalamic nuclei, including the

paraventricular hypothalamic nucleus [61,202]. Rostral

parts of the prelimbic and infralimbic areas, together with

the medial orbital area project to more lateral and

ventrolateral hypothalamus areas [59,61,92,183] (Table 3).

Floyd et al. [61] have argued that the different regions of the

medial prefrontal cortex, which project in a topographical

way to functionally distinct parts of the periaqueductal gray

in the mesencephalon [60], engage in parallel, functionally

distinct ‘emotional motor’ circuits. These ‘emotional motor’

circuits underlie different aspects of integrated behavioral

and autonomic/endocrine responses, such as active and

passive coping with stress [5,61].

Finally, it is worth noting that hypothalamic projections

to the prefrontal cortex are derived from several cell groups,

including histaminergic and melanocortin-containing neur-

ons, but these fiber systems do not provide a clear

dorsoventral distinction between cortical areas within the

medial frontal wall [170].

3.7. Brain stem connections

There appears to be a clear dorsoventral distinction in the

medial prefrontal projections to many brain stem structures

that are reached by these cortcial efferents. As a whole the

medial prefrontal cortex has extensive brain stem projec-

tions, including those to the superior colliculus, peri-

aqueductal grey, peribrachial nuclei, nucleus of the

solitary tract, motor nucleus of the vagus, nucleus ambiguus

and various other brain stem regions including parts of the

caudal reticular formation [60,92,135,163,183,202]. In

addition, the rat medial prefrontal cortex extends projec-

tions to the spinal cord [202]. However, the ventrally

located infralimbic and prelimbic areas project most heavily

to autonomic centers in pons and medulla, while the more

dorsally located anterior cingulate area has more projections

to the spinal cord, in particular the autonomic intermedio-

lateral cell column [202]. The results of the study by Floyd

et al. [60] on the prefrontal projections to the periaqueductal

gray further suggest that, in addition to a dorsoventral

gradient, there is also a rostrocaudal distinction within the

medial prefrontal projections. These authors showed that the

rostral parts of the prelimbic, infralimbic and medial orbital

areas target most strongly the ventrolateral periaqueductal

gray, whereas the caudal parts of these medial prefrontal

areas reach predominantly the dorsolateral parts of

the periaqueductal gray matter. More dorsal cortical areas

in the medial frontal wall project progressively more dorsal

and lateral in the mesencephalon. Thus, the anterior

cingulate cortex projects most strongly into the most

dorsolateral part of the periaqueductal gray, the adjacent

reticular formation and the deep layers of the superior

colliculus, while the dorsally adjacent FR2 region has the

strongest projections into the superior colliculus [8,60,134,

135,163,164,183] (Table 3). In agreement with a rostro-

caudal distinction, it is particularly the caudal part of the

infralimbic cortex that has distinct connections with the

sympathetic nervous system [210].

Like the rest of the cerebral cortex, the prefrontal cortex

receives serotonergic and noradrenergic inputs from the

raphe nuclei and the locus coeruleus, respectively. In

addition, and unlike most other cortices in the rat, the

prefrontal cortex also receives dopaminergic inputs that are

primarily derived from the ventral tegmental area (see

above and Section 4.1). Further, cell groups in the

dorsolateral tegmentum provide the prefrontal cortex with

a brain stem cholinergic input [174] (see also Section 4.1). It

is of interest in this context that the medial prefrontal cortex

is rather unique in projecting back to these cholinergic and

monoaminergic cell groups in the brain stem [77,81,92,97,

98,115,179,183] (Table 3). For example, retrograde tracing

experiments, some of which in combination with extra-

cellular recordings, have shown rather selective and strong

bilateral projections from the infralimbic and dorsal

peduncular cortices to the dorsal raphe nucleus [81]. Thus,

in general the ventral prelimbic and infralimbic areas

provide a much stronger input to these brain stem nuclei

compared with the anterior cingulate and FR2 areas.

3.8. Towards a dorso-ventral distinction within the medial

prefrontal cortex based upon neuroanatomical

characteristics

On the basis of the above-discussed patterns of afferent

and efferent connections, it may be concluded that the

ventral and dorsal parts of the medial prefrontal cortex differ

considerably with respect to their associations with other

parts of the brain (see also Table 3). Whereas the entire

medial wall has its primary thalamic connections with the

mediodorsal nucleus (a main characteristic of the ‘pre-

frontal’ cortex), there are clear differences between the

dorsal (including the dorsal prelimbic, anterior cingulate,

and FR2 areas) and ventral (including the ventral prelimbic

and infralimbic areas) parts with respect to their cortico-

cortical, limbic and subcortical connections. First, there are

important topographical differences with respect to the

projections to the striatum, including shell and core of the

nucleus accumbens (Table 3). Furthermore, while the dorsal

medial prefrontal areas have distinct connections with

sensorimotor and association neocortical areas, the ventral

prefrontal areas virtually lack such connections. The ventral

areas have rather extensive connections with the amygdala

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 569

and temporal, limbic association cortices, while the

connections of the dorsal medial prefrontal areas with

these regions are much more restricted. In addition, the

ventral prefrontal cortices project extensively to ‘limbic’

subcortical structures such as the septum, preoptic and

hypothalamic areas. In contrast, the contribution from

dorsal prefrontal cortices to these areas is rather limited.

Finally, the ventrally located areas in the medial prefrontal

cortex exert a much stronger influence on brain stem

monoaminergic cell groups than the dorsal areas (Table 3).

4. Are there neurochemical/histochemical grounds

for a dissociation between subterritories of the medial

prefrontal cortex in the rat?

4.1. Neurochemistry studies

4.1.1. Dopamine

As mentioned above (Section 3.4), studies have elegantly

demonstrated that the dopamine transporter is densely

distributed in the anterior cingulate cortex and only sparsely

into the deep layers of the prelimbic cortex [184]. Moreover,

these observations are consistent with the lower immunor-

eactivity and mRNA signal for the dopamine transporter in

the ventral tegmental area compared with the substantia

nigra [30,186]. Both anatomical [204] and neurochemical

[195] studies indicate that the highest density of dopamine

innervation is found in the prelimbic cortex. Consistent with

these observations, a series of in vivo microdialysis studies

[82,83,85,119] have also shown that basal dopamine levels

are significantly higher in the ventral medial prefrontal

cortex (ventral prelimbic and infralimbic areas) compared

with the dorsal medial prefrontal cortex (anterior cingulate

and dorsal prelimbic areas). Altogether, these findings

suggest that the ventral prelimbic and infralimbic cortices

have a more intense dopaminergic innervation, a lower

content of dopamine transporter and, hence, a reduced

dopamine uptake capacity and a higher concentration

gradient of extracellular dopamine. In contrast, the distri-

bution of dopamine transporter-labelled axons is higher in

the dorsal anterior cingulate cortex, which has an increased

dopamine uptake capacity and, in combination with a less

intense dopamine innervation, a lower concentration

gradient of extracellular dopamine. One alternative expla-

nation for the differential basal release properties of

dopamine in subregions of the medial prefrontal cortex is

that the serotonin and norepinephrine transporters (SERT

and NET, respectively) participate in the uptake and

clearance of dopamine. A major role of SERT in the

clearance of dopamine is unlikely since it has a lower

affinity for dopamine compared with both DAT and NET

[91]. However, the potential role of NET to the region-

dependent uptake and clearance of dopamine cannot be

ruled out [119]. It has been shown that externally applied

dopamine is taken up primarily by norepinephrine terminals

through NET in the dorsal medial prefrontal cortex, whereas

DAT is the major actor in clearing the extracellular

dopamine in the infralimbic cortex [26]. The question of

whether NET affects the clearance rate of dopamine under

basal conditions in subregions of the medial prefrontal

cortex requires further investigations.

4.1.2. Serotonin

The serotonergic innervation of the cerebral cortex

originates mainly from the raphe nuclei [104,212,213],

which send two morphologically distinct classes of fibers:

fine axons with small varicosities originate from the dorsal

raphe nucleus whereas beaded axons characterized by

large, spherical varicosities arise from the median raphe

nucleus (see also Section 3.7). Fine serotonin axon

terminals are widely distributed among all cortical layers,

although variations in density and laminar distribution are

observed between different cortical areas [104,212,213].

Beaded serotonin axon terminals are found primarily in the

outer cortical layers [212,213]. As indicated above (Section

3.8), the infralimbic and dorsal peduncular cortices project

strongly to the dorsal raphe nucleus [81,148]. Thus, these

findings clearly demonstrate that the anatomical pathway

between the medial prefrontal cortex and the raphe nuclei

in the rat involves predominantly the ventral part of the

medial prefrontal cortex (infralimbic, ventral prelimbic,

and dorsal peduncular cortices) and the dorsal raphe

nucleus. Recent ex vivo neurochemistry studies [32]

seem to confirm these ventro-dorsal differences in both

the left and right hemispheres of low and high impulsive

rats. However, dialysis experiments failed to reveal such

difference for serotonin [84]. Interestingly, increased 5-HT

outflow occuring specifically in the prelimbic cortex has

been associated with impulsive behavior as assessed by the

rat’s capacity to inhibit premature responding in a visual

attentional task [32].

4.1.3. Norepinephrine

The medial prefrontal cortex receives noradrenergic

innervation from the locus coeruleus. The anterior cingulate

cortex has the lowest density of norepinephrine innervation

in the neocortex, whereas the granular retrosplenial cortex

(i.e. posterior cingulate cortex) receives the densest

norepinephrine axon terminals [130]. The density of

norepinephrine projections in the prelimbic cortex falls

between that of the anterior and posterior cingulate cortices

[130]. We have seen (Section 3.7) that the locus coeruleus

receives reciprocal innervation from the medial prefrontal

cortex and that there is a tendency for the prelimbic and

infralimbic areas to provide a stronger input to brain stem

nuclei compared with the anterior cingulate and FR2 areas.

Interestingly, stimulation of the locus coeruleus has been

shown to produce a decrease in basal neuronal activity [118]

and an increase in extracellular levels of dopamine in the

prelimbic/infralimbic cortex [101]. Altogether, these

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579570

findings suggest that, in the prelimbic/infralimbic cortex,

norepinephrine may increase dopamine release.

4.1.4. Acetylcholine

The cholinergic innervation of the cerebral cortex

originating from the caudal part of the basal nucleus is

diffuse in nature and terminates in all cortical layers [54,109,

114,171,214,215]. These observations are consistent with

studies indicating that both basal and stimulated acetyl-

choline releases are similar in the prefrontal and frontopar-

ietal cortices [90]. The sensitivity of neurons to the

microiontophoretic application of acetylcholine in

the dorsolateral prefrontal cortex of the monkey is not

homogeneous between cortical layers [3,93,176], suggesting

that acetylcholine may differentially influence the neuronal

activity of specific laminae of the dorsolateral prefrontal

cortex. In fact, the microinfusion of amphetamine by reverse

microdialysis increases dialysate acetylcholine levels in a

dose-dependent manner only in the infralimbic cortex [84].

Recent studies have elegantly demonstrated that microinfu-

sions of the muscarinic cholinergic antagonist scopolamine

into the prelimbic/infralimbic cortices, but not the anterior

cingulate cortex, impair spatial working memory in a dose-

dependent manner [155]. The scopolamine-induced effect on

spatial working memory was also attenuated by the

concomitant administration of the muscarinic agonist

oxotremorine in the same subregion of the medial prefrontal

cortex [155], suggesting that the working memory impair-

ment produced by scopolamine is likely due to the blockade

of muscarinic cholinergic receptors in the prelimbic/infra-

limbic cortices. In fact, the activation of cholinergic neurons

originating from the nucleus basalis magnocellularis and the

mesopontine laterodorsal tegmental nucleus [66,110,114,

174] and the resulting release of acetylcholine (ACh) in the

target prefrontal cortical areas is associated with electro-

encephalographic desynchronization [29,100,149,150,160]

and locomotor activity [36]. Thus, the activation of the basal

forebrain cholinergic neurons projecting towards the medial

prefrontal cortex results in arousal which, in turn, is required

for the processing of sensory, motor, and cognitive

information [52,53,152,155,171]. The available evidence

thus supports the contention that while the release of

acetylcholine in the medial prefrontal cortex heightens

arousal, which is required to process both sensorimotor

information [171] and spatial working memory [155], the

type of cognitive processes that acetylcholine enhances

depends, at least in part, on specific subterritories within the

medial prefrontal cortex.

4.2. Expression of immediate-early genes

It has been shown that whereas typical and atypical

antipsychotics are both effective in treating the positive

symptoms of schizophrenia, atypical antipsychotics show

considerably greater efficacy in alleviating the negative

symptoms [103,124]. Furthermore, atypical antipsychotics

produce less extrapyramidal motor side effects than typical

antipsychotics [4,19,25]. The etiology of negative

symptoms and cognitive dysfunction of schizophrenia

have been associated with dopaminergic hypofunction in

the medial prefrontal cortex [34,72,209]. It has been

proposed that a correlation exists between the increase in

extracellular dopamine in the medial prefrontal cortex vs.

striatum and the efficacy vs. side effect profile of

antipsychotic drugs [108,127,137,145,207]. Noteably, all

clinically effective antipsychotics can increase Fos

expression in the shell of the nucleus accumbens, however

only clozapine has been shown to produce a significant

increase in Fos-like immunoreactivity in pyramidal neurons

of the deep layers (V and VI), but not superficial layers (II

and III) of the infralimbic and prelimbic cortices [43].

Furthermore, there was a sharp dorso-ventral gradient in the

number of Fos-immunoreactive neurons with no changes in

Fos-immunoreactive neurons in the dorsal part of the

anterior cingulate cortex (area 24b) [43]. These findings

point towards the infralimbic and prelimbic subregions of

the medial prefrontal cortex as unique sub-circuits involved

in the effects of atypical, but not typical antipsychotic drugs.

The activation of Fos expression is also associated

with stressful stimuli [44,51,177,190] or exposure to

novelty [20,74,116,185]. During the acquisition of con-

ditioned fear, strong Fos-like immunoreactivity has been

shown in the infralimbic and prelimbic cortices, but not in

the anterior cingulate and M1 motor cortex [131].

Furthermore, footshock-induced stress was shown to

produce significant activation of Fos-like immunoreactive

neurons in the deep layers of the prelimbic/infralimbic

cortex [132]. In addition, the administration of the

benzodiazepine agonist, lorazepam, and partial agonist,

bretazenil could prevent this stress-induced activation in

Fos-like immunoreactivity [132]. Finally, the systemic

administration of four prototypic panicogenic–anxiogenic

drugs, including the benzodiazepine inverse agonist FG-

7142, the nonselective 5-HT2C receptor agonist m-chlor-

ophenyl piperazine, the adenosine receptor antagonist

caffeine, and the alpha2-adrenoceptor antagonist yohimbine,

was shown to produce a significant increase in Fos-like

immunoreactivity mainly in the prelimbic/infralimbic

cortex and central nucleus of the amygdala [189].

Furthermore, ibotenic acid lesions of the prelimbic/infra-

limbic cortex were reported to potentiate the anxiogenic

effect of FG-7142 in rats [94]. It is worth noting here that

dopamine metabolism is selectively increased in the ventral

subregion of the medial prefrontal cortex after pentylenete-

trazole (PTZ) discrimination training [16] thus suggesting

that dopamine transmission in the prelimbic/infralimbic

cortex is involved in the anxiogenic effects of PTZ [16].

Unilateral, low intensity electrical stimulation of the

ventral prelimbic and infralimbic cortices can produce a

viscero-motor depressor response (reduction in blood

pressure and heart rate as well as alterations in gastric

mobility), which is associated with increased expression of

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 571

Fos-like immunoreactive neurons in both the ventral part of

the medial prefrontal cortex and regions of the medulla

oblongata ipsilateral to the site of electrical stimulation

[141]. These findings thus suggest that a cortico-solitary

pathway that may be critical to promote recovery from

stress [138] mediates the sympatho-inhibitory responses

elicited by stimulation of the ventral prelimbic/infralimbic

cortex.

Recent experiments have also shown that in rats

having expressed sensitization following the five daily

administration of amphetamine, the estimated number of

Fos-like immunoreactive cells was significantly enhanced

in the dorsal (anterior cingulate and dorsal prelimbic),

but not in the ventral (ventral prelimbic and infralimbic)

part of the medial prefrontal cortex [86]. These findings

corroborate previous studies suggesting a key role of the

dorsal part of the medial prefrontal cortex in behavioral

sensitization to drugs of abuse [151,197]. They are also

in line with recent studies showing that priming

injections of cocaine in experienced cocaine self-admin-

istering rats increase Fos protein in the anterior cingulate

cortex [136].

4.3. Towards a dorso-ventral distinction within the medial

prefrontal cortex based upon neurochemical and

histochemical characteristics

In addition to significant differences in functional and

neuroanatomical characteristics, the ventral and dorsal

parts of the medial prefrontal cortex also differ

considerably with respect to neurochemical and histo-

chemical features. The anterior cingulate cortex seems to

have the highest dopamine uptake capacity and appears

to be most sensitive to drug-induced sensitization and

drug priming in experienced self-administering rats. In

contrast, the prelimbic/infralimbic cortex has a reduced

dopamine uptake capacity and is most responsive to

neurochemical and/or histochemical changes produced by

atypical antipsychotic drugs, anxiogenic drugs and

conditioned fear stimuli. In the prelimbic/infralimbic

cortex, dopamine alone or in synergy with norepi-

nephrine may be related to anxiogenesis and stress-

triggered relapse to drug seeking behavior, enhanced

serotonergic function seems to be associated with

impulsive behavior, and enhanced cholinergic trans-

mission appears to improve spatial working memory.

Once again, the prelimbic/infralimbic cortex has a key

role in mediating stress-related events. This is further

supported by the tendency of the prelimbic and

infralimbic areas to provide a stronger input to mono-

aminergic and autonomic-related brain stem nuclei

compared with the anterior cingulate cortex. Furthermore,

the activation of a prelimbic/infralimbic-solitary pathway

triggers sympatho-inhibitory responses that may be

critical for recovery from stress.

5. Conclusions

The present work reviewed behavioral, neuroanatomical,

neurochemical and histochemical evidence to support the

existence of a dorso-ventral dissociation within the rat

medial prefrontal cortex. The overview of the connectivity

of the medial prefrontal cortex leads to the conclusion that

this part of the prefrontal cortex can be subdivided not only

on the basis of cytoarchitectonics, but also on the basis of

differences in connectivity patterns. Borders of cortical

areas with similar patterns of efferent and/or afferent

connectivity do not in all cases adhere to the boundaries

of cytoarchitectonically defined areas. We have described

that there is a main distinction between the dorsal and

ventral parts of the medial prefrontal cortex, the dorsal part

including the FR2, dorsal anterior cingulate and dorsal

prelimbic areas, and the ventral part encompassing the

infralimbic, medial orbital and ventral prelimbic areas.

Some of the distinctive connections of the ventral vs.

dorsal subregions of the medial prefrontal cortex can be

summarized as follows. First, ventrally located areas

include projections to the shell of the nucleus accumbens.

In addition, the feedback projections from the medial

prefrontal cortex to the ventral tegmental area arise from

both the prelimbic and infralimbic cortices, but not from the

dorsal part of the medial prefrontal cortex [8,182,183,194].

Accordingly, changes in the basal tone of dopamine in the

ventral subregion of the medial prefrontal cortex may also

affect feedback mechanisms via cortical-ventral tegmental-

accumbens projections. Although electrophysiological evi-

dence supports the idea that the iontophoretic administration

of dopamine has a general inhibitory effect on the

spontaneous firing of medial prefrontal cortex neurons

[58,153,181] that could be mediated indirectly via acti-

vation of GABAergic interneurons [146], recent studies

suggest that the action of dopamine on pyramidal neurons of

the medial prefrontal cortex is neither excitatory nor

inhibitory [217]. In fact, the action of dopamine depends

on a variety of factors including the type and characteristics

of pyramidal neocortical neurons that can be found in the

deep layers of the medial prefrontal cortex (regular spiking,

intrinsic bursting, repetitive oscillatory bursting, and

intermediate cells), the particular location of the neuron

within the deep layers (V–VI) of the medial prefrontal

cortex (dorso-ventral topography), the differential ionic

conductances in the dendrites and soma, the membrane

potential range at which the neuron is operating, and the

strength of cortico-cortical (apical) and subcortical (basal)

synaptic inputs to the pyramidal cells located in the deep

layers of the medial prefrontal cortex. Each of these factors

could then contribute to the state of the medial prefrontal

cortex network for proper function. Given that a critical

concentration of dopamine is required for normal function

of the medial prefrontal cortex [18,133,175,220], it is

reasonable to proceed on the working hypothesis that a

change in dopamine levels may produce more or less

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579572

selectivity or sharpening of stimuli to apical dendrites and

basal dendrites/soma. In view of the lesion studies reviewed

above, one may suggest that a dopaminergic loop connect-

ing the ventral part of the medial prefrontal cortex and the

ventral striatum is important for aspects of performance

requiring the expression of stimulus-response and stimulus-

reward or action-outcome associations. In contrast, a second

loop, including the dorsal part of the medial prefrontal

cortex and the dorsal striatum/core of the nucleus accum-

bens, might be critical for the formation and maintenance of

a response ‘set’ and stimulus-response associations.

The dorsal medial prefrontal areas have distinct connec-

tions with sensorimotor and association neocortical areas,

the ventral prefrontal areas virtually lack such connections.

In contrast, ventral areas have rather extensive connections

with the amygdala and temporal, limbic association

cortices, while the connections of the dorsal medial

prefrontal areas with these regions are much more restricted.

This latter distinction is rather important given that the

basolateral amygdala complex is a key component for

the learning and expression of auditory fear conditioning

[56,154,165]. We have described above that infralimbic-

dependent mechanisms are responsible for long-term, but

not short-term, extinction memory and that post-training

consolidation of extinction involves the potentiation of tone

inputs to the infralimbic cortex [125]. Thus, extinction-

induced activation of infralimbic neurons might decrease

freezing by dampening the output of the basolateral

amygdala. In support of this hypothesis, prolonged stimu-

lation of the infralimbic cortex prevents increases in blood

pressure and defensive behaviours elicited by stimulation of

the amygdala [2]. Altogether, these findings also suggest

that failure to achieve an adequate level of potentiation in

the infralimbic cortex after extinction might lead to

exaggerated fear responses [89]. This contention seems to

be further supported by the observation that patients with

post-traumatic stress disorder exhibit depressed ventral

medial prefrontal cortex activity correlated with increased

autonomic arousal, when re-exposed to traumatic reminders

[14,180,187]. Furthermore, the central modulation of the

baroreceptor reflex through ventro-prelimbic/infralimbic-

solitary pathways makes the ventral part of the medial

prefrontal cortex a key element of the circuitry that

integrates internal physiological states with salient environ-

mental cues to guide behavior in situations of perceived

threat or exposure to aversive stimuli. If all this holds true,

than pairing reminder stimuli with activation of the ventral

part of the medial prefrontal cortex by using repetitive

transcranial magnetic stimulation [55] might be a useful

therapeutic approach to strengthen extinction of fear. The

regional specificity of the effects of clozapine, but not

typical antipsychotics, and anxiogenic drugs or events in

deep layers of the infralimbic and prelimbic cortices

suggests that the ventral part of the medial prefrontal cortex

may be a unique target for both atypical antispychotic and

anxiolytic drugs.

Another topographical distinction between the anterior

cingulate and prelimbic/infralimbic cortices lies in that the

ventral prefrontal cortices project extensively to ‘limbic’

subcortical structures such as the septum, and medial parts

of the preoptic and hypothalamic areas. In contrast, the

contribution from dorsal prefrontal cortices to these areas is

rather limited. Inputs from the paraventricular thalamic

nucleus are rather exclusive to the ventral areas, as well as

from medial parts of the mediodorsal thalamic nucleus.

Finally, projections from medial prefrontal areas to brain

stem monoaminergic cell groups are stronger from the

ventral compared to the dorsal areas.

The specific connectivity pattern of the ventral part of the

medial prefrontal cortex, which is clearly involved in tasks

such as delayed alternation and reversal learning remains to

be investigated in future studies. These tasks require both

the generation of different responses to the same stimuli that

change their association with reward across trials as well as

the suppression of responses to stimuli previously associ-

ated with reward. Thus, this ventral medial prefrontal

circuitry does not seem to be critical for the acquisition of a

strategy or rule, but is mainly involved in the flexible

shifting to new strategies or rules in spatial or visual-cued

discrimination tasks. Finally, the ventral medial prefrontal

circuitry and in particular the prelimbic/infralimbic-amyg-

dala pathway, should be further investigated for its key role

in stress-related events.

In contrast to the ventral prelimbic/infralimbic cortex, we

have shown that the dorsally located medial prefrontal areas

project primarily to the core of the nucleus accumbens and

medial caudate-putamen, the dorsal and lateral parts of the

preoptic and hypothalamic areas, and sensorimotor related

regions of the cerebral cortex and the brain stem, like the

superior colliculus. These cortical areas receive inputs from

the intralaminar thalamic nuclei and from the lateral

segment of the mediodorsal nucleus [9,76]. It appears that

these dorsal medial prefrontal circuitries are mainly

involved in shifting away from spatial locations previously

associated with reward (response perseveration), attention,

and the ability to adequately plan actions involved in fear

responding. Thus, these results point towards the dorsal

medial prefrontal cortex and its related circuitries as a key

component involved in the temporal patterning of beha-

vioral sequences. Furthermore, the role of these circuitries

in the expression of behavioral sensitization to cocaine and

its related changes in glutamate release in the core of the

nucleus accumbens warrants further investigations.

Additional support for a dorsal-ventral distinction can

also be derived from the observation that cortical

associational connections occur mainly within and between

areas that form either the dorsal or the ventral component

of the medial prefrontal cortex [31] (see also B. Jones,

H.W. Berendse, H.J. Groenewegen and M.P. Witter,

unpublished observations). Finally, additional heterogene-

ities presumably exist within the medial prefrontal

cortex. Apart from the dorsoventral distinction within

C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579 573

the projections to the hypothalamus, a rostrocaudal

gradient has been recognized in these projections [61] as

well as in those to the periaqueductal gray matter [60]. A

rostrocaudal gradient has also been described in the

projections from the hippocampus to the ventral parts of

the medial prefrontal cortex [95]. Furthermore, neurons

projecting to the nucleus of the solitary tract are

predominantly located in the caudal parts of both the

infralimbic and prelimbic areas [134]. Finally, there are

main differences in the connectivity patterns of deep versus

superficial cortical layers in their cortico-cortical and

cortico-subcortical connections [11,69,80].

Altogether, these findings support the idea that the pattern

of innervation of efferent neurons originating from different

laminae of the medial prefrontal cortex and projecting

towards various subcortical regions may provide a functional

segregation for cortical control of subcortical functions. We

have described that there are both chemo-functional and

chemo-anatomical differences in the dorso-ventral axis of the

rat medial prefrontal cortex and that neurons originating from

deep layers of the prelimbic cortex control a different aspect

of subcortical function compared with neurons originating

from the superficial layers of the anterior cingulate cortex.

Such functional compartmentation of the rat medial

prefrontal cortex underlies the importance of focusing

primate and human studies towards homologous cortical

sites included in specific networks upon which the thera-

peutic effects of new antipsychotic, antidepressant and

anxiolytic drugs are manifested (see also Ref. [17]).

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