Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
www.elsevier.com/locate/neubiorev
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
a
Department of Biology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, Via A. Fleming 4, 37135 Verona, Italy
b
Department 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Are there functional grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat? . . .
2.1. Selective lesions of the anterior cingulate/dorsal prelimbic cortices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Selective lesions of the ventral prelimbic/infralimbic cortices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon behavioral characteristics .
3. Are there anatomical grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat? . .
3.1. Cortico-cortical connections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1. Efferent connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2. Afferent connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Connections with basal forebrain, olfactory and limbic structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Connections with basal ganglia structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Connections with dopaminergic cell groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5. Thalamo-cortico-thalamic relationships. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6. Hypothalamic connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7. Brain stem connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon neuroanatomical
characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: þ 39-45-921-9769; fax: þ39-45-921-8047.
E-mail address: christian_a_heidbreder@gsk.com (C.A. Heidbreder).
0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2003.09.003
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4.1.2. Serotonin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.3. Norepinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.4. Acetylcholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Expression of immediate-early genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Towards a dorso-ventral distinction within the medial prefrontal cortex based upon neurochemical and
histochemical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The mammalian prefrontal cortex has been classically
defined and delineated by anatomical criteria such as
cytoarchitectonic features (granular vs. agranular characteristics) [15], connectivity with the mediodorsal thalamic
nucleus [1,6,71,73,76,105,111,161,168], input of dopaminergic fibers from the ventral mesencephalon, or a combination 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),
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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) 555–579
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, neurochemistry 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 dissociation
between 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 heterogeneity. 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 randomforaging task and a delayed win-shift procedure [178]. Such
557
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 activation [188]. Ibotenic acid lesions of the rostral part of the
anterior cingulate cortex, which corresponds to the perigenual 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 eightarm radial maze [63], the development of sensitization to
either cocaine or amphetamine [197], the acquisition of
spatial learning [158], the switching from spatial to visualcued 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/NoGo conditional discrimination task [40], these lesions seem
to selectively disrupt the temporal organization of behavioral 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 avoidance [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],
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C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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
[113]
Deafferentation (unilateral
undercut lesion)
Subpial suction
Density of cannabinoid receptor binding
with receptor-mediated G-protein
Performance on a sequential task
No effect in both the acquisition of visual
discrimination and the reversal learning task.
No effect
[126]
Electrolytic lesion
CER (Freezing)
Decreased efficiency ratio (number of
reinforcements as percentage of number of bar
presses)
Decreased number of reinforcement during the
post-operative retention tests
Acquisition: increased freezing response to both
context and CS þ tests
Extinction: increased amount of time to
extinguish freezing to both the context and
CS þ
Decreased number of avoidance during testing
and increased number of trials to reach criterion
No effect
No effect
No effect
Impaired acquisition; increased perseveration by
nonmatching
Blockade of sensitization to the locomotor
activating effects of cocaine
Blockade of cocaine-induced changes in
glutamate release in the core of the nucleus
accumbens
Rostral ACC: reduction in formalin-induced
aversion
Caudal ACC: no effect
60 –70% decreased binding
Active Avoidance
NMDA lesion
Ibotenic acid lesion
Locomotor activity
8-Arm radial maze
Nonmatching-to-place task in the T-maze
Matching-to-place in the T-maze
Expression of behavioral sensitization to
cocaine
Formalin test and CPP
Density of cannabinoid receptor binding
with receptor-mediated G-protein
Go/No-go delayed conditioned discrimination
task
Spatial delayed alternation task
Quinolinic acid lesion
Lidocaine 2%
Development of behavioral sensitization to
cocaine
Development of behavioral sensitization to
amphetamine
Delayed match-to-sample task with memory
for a 908 right/left turn
12-Arm radial maze
Gastric motility
Arterial blood pressure
Renal, superior mesenteric and iliac arterial
vascular conductance
c-FOS expression
Delayed spatial win-shift
Tetracaine 2%
Random foraging
Spatial learning in the cheeseboard task
Electrical stimulation
[188]
[128]
[63]
[46]
[151]
[99]
[188]
No effect on GTPgs binding
No effect when selection process does not
require temporal organization
Impairment of acquisition of the task based on
temporal organization
No effect
[199]
No effect
[198]
Reduction in working memory performance for
egocentric responses
Slight increase in the spatial locations tasks
No effect
No effect
[156]
No effect
Increased number of across- phase errors
following pre-training injections
Increased number of across- phase errors
following pre-test injections
Increased number of errors on lidocaine test days
Acquisition of spatial learning: no effect
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
[40]
[157]
[143]
[140,141]
[178]
[158]
(continued on next page)
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Table 1 (continued)
Manipulation type
Paradigm
Experimental effect
Reference
Scopolamine (1–10 mg)
12-Arm radial maze
[155]
Acetylcholine (2.5–60 nmol)
Blood pressure/heart rate
No effect on the working memory for spatial
locations
Dose-dependent decrease in blood pressure
(reversal with either atropine (3 nmol) or 4DAMP (6.7 nmol)
No effect on heart rate
[75]
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.
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 nonmatching 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]. Tetrodotoxininduced 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 lateralized 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 subregion 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 infralimbic, 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
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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
[113]
Electrolytic lesion
CER (freezing)
PL þ IL: no effect in the acquisition of visual
discrimination, but impairment in the reversal
learning task
Acquisition: no effect in both context and CS tests
Extinction: increased amount of time to extinguish
freezing to the CS only
Increased number of avoidance during testing
Training (PL): increased latency to step down onto
the electrified grid
Test (PL): no effect
Training (IL): no effect
Test (IL): shorter latencies to step down onto the
electrified grid
Increased activity
PL: decreased time spent in the center of the field
IL: decreased time spent in the center of the field;
decreased ambulations (line crossings)
PL: no effect
IL: no effect
PL þ IL: decreased time spent on the open arms; no
effect on the total number of crossings
Increased number of arm entry errors
Increased RSP to the CS þ
Active avoidance
Passive avoidance
Locomotor activity
Open field
Exploration in a three-compartment CPP box
Elevated plus maze
NMDA lesion
8-Arm radial maze
Respiratory rate (RSP), freezing, ultrasonic
vocalizations (USVs) during CER
Heart rate (HR) and blood pressure (BP) during CER
Nonmatching-to-place task in the T-maze
Matching-to-place in the T-maze
Ibotenic acid lesion
Delayed non-matching to position task (eight-arm
maze)
Navigation task
Morris water maze test
Spontaneous and amphetamine-induced activity
Elevated-plus-maze
Acoustic startle and prepulse inhibition
Sweetened milk consumption
Taste aversion test
Reaction time
Expression of behavioral sensitization to cocaine
Quinolinic acid lesion
Development of behavioral sensitization to cocaine
Development of behavioral sensitization to
amphetamine
Decreased amount of time spent freezing
Decreased USVs
BP: no effect to the CS þ
HR: increased tachycardia to the CS þ
PL þ IL: no effect
PL þ IL: impaired acquisition; general increase in
perseveration; deficit in reversing from matching to
nonmatching
No effect on acquisition
No effect on prospective planning of spatial
responses
No perseverative tendencies
Increased number of errors when increasing delay
from 10 to 40 sec
No effect on learning simple goal-directed tasks
Learning impairment if fixed location has to be
reached from four different start positions
PL þ IL: no effect
PL þ IL: no effect
PL þ IL (right hemisphere): anxiolytic effect;
increased time spent in open arms
PL þ IL: no effect
PL þ IL: no effect
PL þ IL (right hemisphere): increased consumption
of sweetened milk þ quinine
PL þ IL (bilateral): disruption of motor readiness
and altered pattern of premature responses
No effect
No change in glutamate release in the core of the
nucleus accumbens
Blockade (locomotion and rearing, but not
grooming)
No effect
[128,129]
[63]
[96]
[63]
[96]
[63]
[64]
[64]
[46]
[37–39]
[39]
[192]
[102]
[151]
[197,199]
(continued on next page)
561
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
Table 2 (continued)
Manipulation type
Paradigm
Experimental effect
Reference
Development of CPP (cocaine, amphetamine,
morphine, MK801)
Five-choice reaction time task
Blockade of cocaine CPP
[198]
PL þ IL: decreased accuracy, incorrect latency,
omissions and increased perseverative responding
not reversible by the dopamine D2 antagonist
sulpiride
Impairment of working memory for allocentric space
IL: decrease in gastric pressure
IL þ DP: increased vascular conductance
[144]
Lidocaine 2%
12-Arm radial maze
Gastric motility
Arterial blood pressure
Renal, superior mesenteric and iliac arterial vascular
conductance
c-FOS expression
Delayed spatial win-shift
Tetracaine 2%
Random foraging
Delayed spatial win-shift switched to random
foraging
Spatial learning in the cheeseboard task
Electrical stimulation
Place-response learning in cross-maze
Tetrodotoxin (TTX)
Drug- and stress-triggered relapse to cocaine seeking
Scopolamine (1–10 mg)
12-Arm radial maze
IL þ DP: increased c-FOS expression
Increased number of both across- and within-phase
errors following pre-test injections
No effect
Increased number of errors
Acquisition of spatial learning: No effect
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
Acquisition of place learning and shift to response
learning (cross-modal shift): Impairment (increased
trials to reach criterion)
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
PL: blockade of both drug- and stress-induced
reinstatement of cocaine seeking behavior
IL: no effect
Impairment of working memory for spatial locations
(5 and 10 mg) reversible by concomitant
administration of oxotremorine (2 mg)
[157]
[143]
[140,141]
[178]
[158]
[159]
[21]
[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.
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 associated 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
562
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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 progressive 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 subregions 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, cytoarchitectonically 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 collection 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 schematically 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. Furthermore, 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 association 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) 555–579
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 infralimbic 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 Condé 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 associations, or more ventrally located prefrontal areas, predominantly characterized by cortical relationships with limbic
and associational areas, show gradual transitions rather than
sharp boundaries [31,183,205]. Moreover, cortical association 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 topographically 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
563
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 (hippocampus 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. Hippocampalprefrontal 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
564
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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
–
–
–
–
–
††
†
–
†
†
,
–
††
–
–
†
–
–
–
–
–
–
†
,
†
††
††
,
,
††
†
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†
–
–
–
–
,,
,
†
,
†
†††
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,
†
,
††
††
–
–
,
–
–
–
†
,
–
††
††
–
††
†
,
–
–
–
–
–
–
–
†
†
,
†
†††
†††
–
††
†
†
†
,
–
–
–
–
–
,
,
,
†
†††
†††
,
†
†
†
,
,
–
,
–
,
–
†
††
,
†
†††
††
†
,
††
,
,
,
–
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
††
†
†
–
,
†
†
–
†
†
,
†
†
,
–
††
†
†
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–
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,
,
,
–
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–
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–
–
,
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,
–
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†
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,
,
–
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,
–
,
–
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,
,
,
†
†
,
,
,
†
†
,
,
†
†
,
,
†
†
†
†
†
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
†
†††
†††
,
†
†
††
†
†††
†††
†
†
††
††
††
†††
†††
,
,
†
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†††
,
†††
†††
†
†
†
††
††
†††
†††
†
†
††
†††
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
(continued on next page)
565
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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
†
†
†
,
††
†
,
†††
†
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–
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–
,
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–
,
,
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–
–
–
–
–
–
–
–
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
†
†
–
–
–
†
††
–
–
–
–
–
–
–
–
–
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–
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–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
,
Basal ganglia structures
Caudate – putamen intermediate/lateral
Accumbens core/lateral
Accumbens shell/lateral
Olfactory tubercle –striatal
Olfactory tubercle –pallidal
Ventral pallidum
Subthalamic nucleus
†††
††
,
–
–
–
,
††
††
,
,
–
–
,
†††
††
,
,
–
–
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–
–
–
–
†
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–
–
–
–
†
††
–
–
–
–
–
–
Hypothalamus
Preoptic area medial
Preoptic area lateral
Hypothalamus medial
Hypothalamus lateral
Mamillary region
Zona Incerta
–
–
–
,
–
,
,
,
–
,
–
,
,
,
†
†
†
†
–
–
,
,
–
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–
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–
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–
,
–
,
–
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–
–
–
,
–
†
–
–
–
–
–
–
Thalamus
Anterior nuclei
Parataenial nucleus
Mediodorsal nucleus
Lateral dorsal nucleus
Lateral posterior
Midline thalamic nuclei PV
Midline thalamic nuclei Re
†
†
†††
†
†
,
,
†
–
††
†
†
††
††
†
†
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†
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†
,
††
††
,
†††
†
††
–
††
†††
,
††
†
†
–
†
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
–
–
–
–
†
–
†
††
,
†
–
–
†
–
(continued on next page)
566
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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
–
††
††
††
,
,
,
,
,
†
,
–
†
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–
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–
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,
,
,
–
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–
,
–
–
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–
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,
†
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††
†
,
†
†
,
†
,
amygdaloid nucleus and the periamygdaloid cortex [106,
120,121]. The projections from the basal amygdaloid
complex to the medial prefrontal cortex show a topographical arrangement [27]. The caudal parts of the parvicellular 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 Groenewegen, 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 projections 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, corticostriatal 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 projections 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 caudateputamen, 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 accumbens, whereas more dorsal prefrontal regions project to the
core of this nucleus and the dorsally adjacent caudateputamen. 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—thalamocortical 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 pallidothalamo-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
567
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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
†††
†
†
†
,
†
†
†
–
,
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†
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–
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†
†
††
–
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
–
,
,
,
–
,
–
–
,
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†
†
†
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,
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.
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 organization 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 hypothalamic 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 innervation 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].
568
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
influence on dopaminergic neurons in the ventral mesencephalon [8,24,92,183]. Ventral areas in the medial prefrontal
cortical areas do project more densely to these dopaminergic cell groups [182,183,194] (see also Table 3).
3.5. Thalamo-cortico-thalamic relationships
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.
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 infralimbic areas, originate predominantly from the ventral
tegmental area (A10 cell group). Recent immunohistochemical studies have demonstrated that the dopamine
transporter is relatively abundantly expressed on dopaminergic 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 differential 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
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 infralimbic 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
C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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 neurons, 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 projections, including those to the superior colliculus, periaqueductal 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 projections 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 intermediolateral 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
569
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 rostrocaudal 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 extracellular 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 ‘prefrontal’ 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 corticocortical, 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
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C.A. Heidbreder, H.J. Groenewegen / Neuroscience and Biobehavioral Reviews 27 (2003) 555–579
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 immunoreactivity 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 distribution 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 explanation 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 regiondependent 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) 555–579
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 acetylcholine releases are similar in the prefrontal and frontoparietal 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 microinfusions of the muscarinic cholinergic antagonist scopolamine
into the prelimbic/infralimbic cortices, but not the anterior
cingulate cortex, impair spatial working memory in a dosedependent 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 impairment produced by scopolamine is likely due to the blockade
of muscarinic cholinergic receptors in the prelimbic/infralimbic 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 electroencephalographic 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
571
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 conditioned 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 FG7142, the nonselective 5-HT2C receptor agonist m-chlorophenyl 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/infralimbic 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 pentylenetetrazole (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
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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-administering 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 histochemical 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 norepinephrine may be related to anxiogenesis and stresstriggered relapse to drug seeking behavior, enhanced
serotonergic function seems to be associated with
impulsive behavior, and enhanced cholinergic transmission 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 monoaminergic 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 tegmentalaccumbens projections. Although electrophysiological evidence 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 activation 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) 555–579
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 connecting 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 stimulusreward 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 accumbens, might be critical for the formation and maintenance of
a response ‘set’ and stimulus-response associations.
The dorsal medial prefrontal areas have distinct connections 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 infralimbicdependent 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, extinctioninduced activation of infralimbic neurons might decrease
freezing by dampening the output of the basolateral
amygdala. In support of this hypothesis, prolonged stimulation 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/infralimbicsolitary pathways makes the ventral part of the medial
prefrontal cortex a key element of the circuitry that
integrates internal physiological states with salient environmental 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.
573
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 associated 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-amygdala 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 behavioral 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 heterogeneities presumably exist within the medial prefrontal
cortex. Apart from the dorsoventral distinction within
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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 therapeutic effects of new antipsychotic, antidepressant and
anxiolytic drugs are manifested (see also Ref. [17]).
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The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics
Neuroscience & Biobehavioral Reviews, 2003
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