Brain Struct Funct (2007) 212:149–179
DOI 10.1007/s00429-007-0150-4
ORIGINAL ARTICLE
Anatomical analysis of afferent projections to the medial
prefrontal cortex in the rat
Walter B. Hoover Æ Robert P. Vertes
Received: 27 February 2007 / Accepted: 4 June 2007 / Published online: 27 July 2007
Springer-Verlag 2007
Abstract The medial prefrontal cortex (mPFC) has been
associated with diverse functions including attentional
processes, visceromotor activity, decision making, goal
directed behavior, and working memory. Using retrograde
tracing techniques, we examined, compared, and contrasted
afferent projections to the four divisions of the mPFC in the
rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices.
Each division of the mPFC receives a unique set of afferent
projections. There is a shift dorsoventrally along the mPFC
from predominantly sensorimotor input to the dorsal mPFC
(AGm and dorsal AC) to primarily ‘limbic’ input to the
ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the
cortex (and associated thalamic nuclei) representing all
sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed
actions. In contrast with the dorsal mPFC, the ventral
mPFC receives significantly less cortical input overall and
afferents from limbic as opposed to sensorimotor regions of
cortex. The main sources of afferent projections to PL/IL
are from the orbitomedial prefrontal, agranular insular,
perirhinal and entorhinal cortices, the hippocampus, the
claustrum, the medial basal forebrain, the basal nuclei of
amygdala, the midline thalamus and monoaminergic nuclei
of the brainstem. With a few exceptions, there are few
projections from the hypothalamus to the dorsal or ventral
mPFC. Accordingly, subcortical limbic information mainly
W. B. Hoover R. P. Vertes (&)
Center for Complex Systems and Brain Sciences,
Florida Atlantic University,
Boca Raton, FL 33431, USA
e-mail: Vertes@ccs.fau.edu
reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of
afferent (as well as efferent) projections, PL is positioned
to serve a direct role in cognitive functions homologous to
dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates.
Keywords Claustrum Nucleus reuniens Memory Mediodorsal nucleus of thalamus Insular cortex
Abbreviations
AA
Anterior area of amygdala
AC
Anterior cingulate cortex
ACC
Nucleus accumbens
AD
Anterodorsal nucleus of thalamus
AGm
Medial agranular (frontal) cortex
AGl
Lateral agranular (frontal) cortex
AH
Anterior nucleus of hypothalamus
AI,d,p,v
Agranular insular cortex, dorsal, posterior,
ventral divisions
AM,d
Anteromedial nucleus of thalamus, dorsal
division
AON, m,v Anterior olfactory nucleus, medial, ventral
parts
AQ
Cerebral aqueduct
APN
Anterior pretectal nucleus
AUD
Auditory cortex
AV
Anteroventral nucleus of thalamus
BF
Basal forebrain
BLA
Basolateral nucleus of amygdala
BMA,p
Basomedial nucleus of amygdala, posterior
part
BST
Bed nucleus of stria terminalis
123
150
CA1,3
CB
CC
CEA
CL
CLA
CLi
CM
COA
CP
CUN
DBh
DG
DI
DR
EC,l,m
ECT
EN
FP,l,m
FR
FS
GI
GP
HF
IAM
IC
IF
IL
IMD
INC
IP
LA
LC
LD
LDT
LG,d
LH
LHy
LM
LO
LP
LPO
LS
LV
MA
MB
MD
MEA
MFB
MG,v
MH
MO
123
Brain Struct Funct (2007) 212:149–179
Field CA1 and CA3 of Ammon’s horn
Cinguum bundle
Corpus callosum
Central nucleus of amygdala
Central lateral nucleus of the thalamus
Claustrum
Central linear nucleus
Central medial nucleus of thalamus
Cortical nucleus of amygdala
Caudate-putamen
Cuneiform nucleus
Nucleus of diagonal band, horizontal limb
Dentate gyrus of hippocampus
Dysgranular insular cortex
Dorsal raphe nucleus
Entorhinal cortex, lateral, medial divisions
Ectorhinal cortex
Endopiriform nucleus
Frontal polar cortex, lateral, medial divisions
Fasciculus retroflexus
Fundus of the striatum
Granular insular cortex
Globus pallidus
Hippocampal formation
Interanteromedial nucleus of thalamus
Inferior colliculus
Interfascicular nucleus
Infralimbic cortex
Intermediodorsal necleus of thalamus
Insular cortex
Interpeduncular nucleus
Lateral nucleus of amygdala
Locus coeruleus
Lateral dorsal nucleus of thalamus
Laterodorsal tegmental nucleus
Lateral geniculate nucleus, dorsal division
Lateral habenula
Lateral hypothalamus
Lateral mammillary nucleus
Lateral orbital cortex
Lateral posterior nucleus of thalamus
Lateral preoptic area
Lateral septum
Lateral ventricle
Magnocellular preoptic nucleus
Mammillary bodies
Mediodorsal nucleus of thalamus
Medial nucleus of the amygdala
Medial forebrain bundle
Medial geniculate nucleus, ventral division
Medial habenula
Medial orbital cortex
mPFC
MPO
MR
MRF
MS
MT
NI
NLL
NP
OC,1,2
OT
PA
PAG
PAp
PARA
PB, l, m
PC
PF
PH
PIR
PL
PN5
PO
POST
PPT
PRC
PRE
PT
PV
RAM
RE
RF
RH
RLi
RM
RN
RPC
RPO
RSC
RR
RT
SC
SF
SI
sm
SM
SN,c,r
SSI
SSII
SUB,d,v
Medial prefrontal cortex
Medial preoptic area
Median raphe nucleus
Mesencephalic reticular formation
Medial septum
Mammillothalamic tract
Nucleus incertus
Nucleus of lateral lemniscus
Nucleus of pons
Occipital cortex, primary and secondary
divisions
Olfactory tubercle
Posterior nucleus of amygdala
Periaqueductal gray
Posterior parietal cortex
Parasubiculum of HF
Parabrachial nucleus, lateral, medial divisions
Paracentral nucleus of thalamus
Parafascicular nucleus
Posterior nucleus of hypothalamus
Piriform cortex
Prelimbic cortex
Principal sensory nucleus of trigeminal nerve
Posterior nucleus of thalamus
Postsubiculum of HF
Pedunculopontine tegmental nucleus
Perirhinal cortex
Presubiculum of HF
Paratenial nucleus of thalamus
Paraventricular nucleus of thalamus
Radial arm maze
Nucleus reuniens of thalamus
Rhinal fissue
Rhomboid nucleus of thalamus
Rostral linear nucleus
Raphe magnus
Red nucleus
Nucleus pontis caudalis
Nucleus pontis oralis
Retrosplenial cortex
Retrorubral area
Reticular nucleus of thalamus
Superior colliculus
Septofimbrial nucleus
Substantia innominata
Stria medullaris
Submedial nucleus of thalamus
Substantia nigra, pars compacta, pars
reticulata
Primary somatosensory cortex
Secondary somatosensory cortex
Subiculum, dorsal, ventral parts
Brain Struct Funct (2007) 212:149–179
SUM
TE
TR
TT,d,v
V3
V4
VAL
VB
VLO
VM
VO
VTA
ZI
Supramammillary nucleus
Temporal cortex
Amygdalo-piriform transition zone
Taenia tecta, dorsal, ventral parts
Third ventricle
Forth ventricle
Ventral anterior-lateral complex of thalamus
Ventrobasal complex of thalamus
Ventrolateral orbital cortex
Ventral medial nucleus of thalamus
Ventral orbital cortex
Ventral tegmental area
Zona incerta
Introduction
The prefrontal cortex (PFC) of the rat has been divided into
medial, orbital and lateral parts (Ongur and Price 2000).
The medial PFC (mPFC) consists of the four main divisions which from dorsal to ventral are the medial agranular
(AGm) (or medial precentral), the anterior cingulate (AC),
the prelimbic (PL), the infralimbic (IL) cortices (Berendse
and Groenewegen 1991; Ray and Price 1992; Ongur and
Price 2000; Heidbreder and Groenewegen 2003).
The mPFC has been associated with diverse functions
including oculomotor control (frontal eye fields), attentional processes, visceromotor activity, decision making,
goal directed behavior, and working memory (Fuster 1989;
Kolb 1990; Neafsey 1990; Goldman-Rakic 1994; Petrides
1998; Repovs and Baddeley 2006). Dorsal regions of
mPFC (AGm and AC) have been implicated in various
motor behaviors, while ventral regions of mPFC (IL and
PL) have been associated with diverse emotional, cognitive, and mnemonic processes (Heidbreder and Groenewegen 2003).
The IL has been shown to profoundly influence visceral/
autonomic activity. IL stimulation produces changes in
respiration, gastrointestinal motility, heart rate, and blood
pressure (Terreberry and Neafsey 1983; Burns and Wyss
1985; Hurley-Gius and Neafsey 1986; Verberne et al.
1987; Hardy and Holmes 1988). IL is viewed as a visceromotor center (Hurley-Gius and Neafsey 1986; Neafsey
1990). PL, on the other hand, has been implicated in
cognitive processes. PL lesions have been shown to produce pronounced deficits in delayed response tasks (Brito
and Brito 1990; Seamans et al. 1995; Delatour and GisquetVerrier 1996, 1999, 2000; Floresco et al. 1997; Ragozzino
et al. 1998), similar to those seen with lesions of the dorsolateral PFC of primates (Kolb 1984; Goldman-Rakic
151
1994; Barbas 1995, 2000; Groenewegen and Uylings
2000).
Although efferent projections from the mPFC have been
well described in several species (Room et al. 1985; Sesack
et al. 1989; Reep et al. 1990, 2003; Chiba et al. 2001;
Hurley et al. 1991; Takagishi and Chiba 1991; Buchanan
et al. 1994; Guandalini 1998; Vertes 2002, 2004; Cheatwood et al. 2003; Gabbott et al. 2003, 2005), few reports
have examined afferent projections to the mPFC, specifically to its various subdivisions. To our knowledge, only a
single study (Conde et al. 1995) has compared afferents to
the four divisions of the mPFC: IL, PL, AC, and AGm.
While Conde et al. (1995) described inputs to subregions of
the mPFC in the rat, their injections were relatively large
and as they indicated often included more than one mPFC
field. By making discrete injections of the retrograde tracer,
Fluorogold (FG), into select subfields of the mPFC, we
sought to define patterns of (differential) input to the IL,
PL, AC, and AGm cortices in rats. We show that each of
the mPFC subfields exhibited a quite unique pattern of
afferent projections. These distinctive sets of afferents
undoubtedly contribute to functional differences among
mPFC fields.
Materials and methods
Sixty-two male Sprague-Dawley rats (Charles River, Wilmington, MA) weighing 350–450 g were injected with the
retrograde fluorescent tracer FG (Fluorochrome, Denver,
CO). These experiments were approved by the Florida
Atlantic University Institutional Animal Care and Use
Committee and conform to all federal regulations and
National Institutes of Health guidelines for the care and use
of laboratory animals.
Fluorogold was dissolved in a 0.1 M sodium acetate
buffer (pH 4.0–5) to yield a 4–5% concentration. Rats were
anesthetized using a 75 mg/kg dose of sodium pentobarbital. Single injections of FG were made iontophoretically
using glass micropipettes with outside tip diameters of 25–
50 lm into one of four medial prefrontal cortical areas in
separate rats: AGm, the AC, PL, and IL cortices. Positive
direct current (5–10 lA) was applied through a Grass
stimulator (model 88) coupled with a high-voltage stimulator (FHC, Bowdoinham, ME) at 2 s ‘on’/2 s ‘off’ intervals
for 2–10 min. Following a survival time of 7 days, rats were
deeply anesthetized with sodium pentobarbital and perfused
transcardially with 100 ml of a heparinized saline wash
followed by 450 ml of fixative [4% paraformaldehyde in
0.01 M sodium phosphate buffer (PB), pH 7.4]. The brains
were then removed and stored for 48 h in a sucrose solution
(30% sucrose in 0.1 M PB) at 4C. Following this, 50 lm
coronal sections were taken on a freezing microtome and
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152
collected in 0.1 M PB and stored at 4C. Six series of
sections were taken yielding a representative collection of
sections that were 300 lm apart. For the reaction, sections
of a representative series were incubated in a sodium
borohydride solution (1% sodium borohydride in 0.1 M PB)
for 30 min, and washed with 0.1 M PB four times at 6 min
each (4 · 6 min). The sections were then blocked in a Trissaline solution [0.5% bovine serum albumen (BSA) (Sigma
Chemicals, St. Louis, MO) 0.25% Triton X-100 (Sigma
Chemicals) in 0.1 M Tris-saline, pH 7.6] for 1 h. Following
the blocking procedure, the sections were incubated for
48 h at room temperature in primary antiserum directed
against FG (rabbit anti-FG) (Fluorochrome, LLC) at a
concentration of 1:200 in diluent (0.1% BSA and 0.25%
Triton X-100 in 0.1 M Tris-saline solution). Following
incubation in the primary antiserum, sections were washed
(4 · 6 min) in 0.1 M PB, and then incubated in a secondary
antiserum (biotinylated goat anti-rabbit IgG) (Vector Labs,
Burlingame CA) at a concentration of 1:400 in diluent for
2 h. Sections were then washed again (4 · 6 min) and
incubated in avidin-biotin complex (Vector Labs) at a 1:100
concentration in diluent for 1 h. After a final set of
4 · 6 min rinses, the peroxidase reaction product was
visualized by incubation in a solution containing 0.022% of
3,3¢ diaminobenzidine (DAB, Aldrich, Milwaukee, WI),
0.015% nickel chloride (NiCl), and 0.003% H2O2 in TBS
for 6 min. Sections were then rinsed again in PBS
(3 · 1 min) and mounted onto chrome-alum gelatin-coated
slides. An adjacent series of representative sections from
each rat was stained with cresyl violet for anatomical reference. Sections were examined using light and darkfield
optics. Injection sites and labeled cells were plotted on
representative schematic coronal sections through the brain
using sections adapted from the rat atlas of Swanson (1998).
The brightfield photomicrographs of labeled cells were taken with a Nikon DXM1200 camera mounted on a Nikon
Eclipse E600 microscope. The photomontages were constructed using Image-Pro Plus 4.5.1.29 (Media Cybernetics
Inc., Silver Spring, MD) and adjusted for brightness and
contrast using Adobe PhotoShop 7.0 (Mountain View, CA).
Results
The pattern of retrogradely labeled cells throughout the
brain following injections of the retrograde tracer, FG, into
the four divisions of the mPFC are described. Four representative cases with injections in the AGm, AC, PL, and IL
cortices are illustrated and discussed in detail. The patterns
of labeling obtained with the four schematically illustrated
cases are representative of patterns found with non-illustrated cases.
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Brain Struct Funct (2007) 212:149–179
Afferents to the medial (frontal) agranular cortex
(AGm)
Figure 1 schematically depicts the pattern of retrogradely
labeled neurons in the brain following a FG injection in
AGm. At anterior levels of the forebrain (Fig. 1a–d),
labeling was pronounced within the medial frontal polar
(FPm), orbital, medial prefrontal, and dorsal agranular
insular (AId) cortices and the CLA, and generally heavier
ipsilateral than contralateral to the injection. Specifically,
significant numbers of labeled neurons were present within
FPm, the medial (MO), ventral (VO), ventrolateral (VLO)
and lateral (LO) orbital cortices, the AGm, AC, PL and IL
of the mPFC and the AId. Labeled cells of FPm, AGm and
AC spread throughout all cortical layers, while those in PL
and IL were largely concentrated in inner layers 5/6. A
small to moderate number of labeled neurons were also
present in the anterior olfactory nucleus (AON) (Fig. 1c).
Further caudally in the anterior forebrain (Fig. 1e–h),
labeled cells continued to be present in some of the same
sites, densely within caudal regions of AGm and AC (all
layers), the CLA and AId. Labeling was present but thinned in PL and IL (Fig. 1e, f). Aside from moderate labeling
in the horizontal limb of the diagonal band nucleus (DBh)
(Fig. 1h), there was a virtual absence of labeled cells in
other regions of the rostral forebrain; that is, within the
lateral (frontal) agranular (AGl), piriform, and anterior
parts of the primary (SSI) and secondary (SSII) somatosensory cortices, the dorsal and ventral striatum (nucleus
accumbens ACC), the olfactory tubercle (OT), and medial
and lateral septum (LS).
At mid-levels of the forebrain (Fig. 1i–l), labeled cells
were localized to dorsomedial and ventrolateral regions of
the cortex, to CLA, to parts of the basal forebrain (BF), to
midline and lateral parts of the thalamus and to the basolateral nucleus of the amygdala (BLA). Cortically, the
AGm, medial parts of AGl, and the posterior agranular
insular cortex (AIp) were densely labeled, whereas AC, the
SSI and the granular insular (GI) cortices were lightly to
moderately labeled. Labeled cells spread throughout the
BF, largely confined to the DBh, ventral pallidum (VP),
substantia innominata (SI), and the magnocellular preoptic
nucleus (MA). Of these, DBh and SI were the most heavily
labeled. Figure 2a, b shows a discrete group of labeled
neurons spanning SI and VP. The location, size and general
morphological characteristics of these neurons suggest that
they may belong to the cholinergic (ACh) population of
neurons of the BF (see Discussion). Within the thalamus,
the nucleus reuniens (RE), paratenial nucleus (PT), and
ventral anterior-lateral complex (VAL) were densely labeled (Fig. 1k, l). A few labeled cells were present within
the medial nucleus of amygdala (MEA) and the lateral
Brain Struct Funct (2007) 212:149–179
A
153
E
FPm
FPl
PL
AId
AGm
AC
MO
PL
SSI
VLO
IL
AId
ACC
AIv
FPm
B
F
AGl
AC
AC
CP
PL
LO
CLA
IL
VO
AId
EN
ACC
PIR
AGm
G
C
AC
AGl
AC
SSI
PL
CP
MO
CLA
AId
AId
ACC
OT
AGm
D
AGm
H
AGl
AC
AC
SSI
PL
CP
CLA
LS
IL
SSII
MS
CLA
PIR
AON
AIp
EN
DBh
FS
OT
Fig. 1 Series of representative rostro-caudally aligned schematic
transverse sections (a–x) depicting the location of retrogradely
labeled cells in the brain produced by a FG injection (c) in the
medial (frontal) agranular cortex (AGm). One dot = one cell. Sections
modified from the rat atlas of Swanson (1998). See list for
abbreviations
hypothalamus (LHy) (Fig. 1k, l). With few exceptions,
labeling was predominantly ipsilateral.
More caudally in the forebrain (Fig. 1m–p), prominent
numbers of labeled neurons were observed over the lateral
convexity of cortex, in CLA, in the midline, intralaminar
and lateral parts of thalamus and in BLA (see Fig. 2c), but
with the exception of a few cells in the posterior nucleus of
the hypothalamus (PH), were noticeably absent in the
hypothalamus. As depicted (Fig. 1m–p), a continuous
stream of labeled neurons extended dorsoventrally from the
retrosplenial (RSC) and motor cortices (AGm and AGl)
through primary/secondary somatosensory and auditory
(AUD) cortices, to AIp, the ectorhinal (ECT) and perirhinal
(PRC) cortices, adjacent to the rhinal fissure. Labeling was
dense in ECT and PRC, particularly in inner layers
(Fig. 1o, p). Several nuclei of the thalamus were strongly
labeled including the paraventricular (PV), mediodorsal
(MD), interanteromedial (IAM), anteromedial (AM),
paracentral (PC), central lateral (CL), central medial (CM)
intermediodorsal (IMD), rhomboid (RH), ventromedial
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154
Brain Struct Funct (2007) 212:149–179
I
M
AGm
AC
SSI
RSC
SSI
LS
CP
IAM
VAL
MS
CLA
GI
RH
CP
RE
SI
VM
AIp
EN
PIR
CEA
LHy
BLA
DBh
BMA
J
AGl
N
AGm
RSC
AC
CP
LD
SSII
SSII
MD
CL
VAL
GP
CLA
RH
BST
RE
SI
AIp
PERI
LHy
EN
LHy
MEA
MA
K
CP
VM
O
AGm
LA
BLA
RSC
SSI
SSI
PV
CP
PT
RT
GI
MD
AM
GP
CEM
CP
RE
AIp
IMD
VB
RE
SI
AH
PERI
ZI
LA
LHy
CEA
BMA
BLA
PIR
L
P
PAp
RSC
RSC
SSI
LP
SSII
CP
AV
PT
PF
PO
IMD
CEM
VAL
AM
RE
AIp
ECT
ZI
SI
CEA
LHy
BLA
PERI
PH
EC
PA
BLA
Fig. 1 continued
(VM), and RE (Fig. 1m–p). Labeling was particularly
pronounced within MD, VM, RH, and RE. Figure 2d
shows a tight cluster of labeled cells ventrally on the
midline in RE, others more diffusely distributed dorsolaterally in RE, and third population dorsally in RH, essentially outlining RH. While the entire rostrocaudal extent of
BLA was densely labeled, considerably fewer labeled
neurons were present in other nuclei of the amygdala,
namely, in the basomedial (BMA) and posterior (PA) nuclei (Fig. 1m–p). Additional lightly labeled sites at these
levels were the lateral posterior nucleus (LP) of thalamus
and the zona incerta (ZI).
123
As observed rostrally, labeling within the cortex at the
caudal diencephalon-rostral midbrain (Fig. 1q–t) was fairly
widespread, but unlike rostrally was now predominantly
confined dorsomedially to RSC, the posterior parietal area
(PAp) and the secondary visual cortex (OC2), and ventrolaterally to the area bordering the rhinal fissure: ECT,
PRC, and the lateral entorhinal cortex (EC). Labeling was
light within temporal (TE) regions of the cortex. Within the
hippocampus, small numbers of reacted neurons were seen
in the postero-dorsal (Fig. 1q–s) and ventral CA1 (Fig. 1r–
t). Subcortically, labeling was mainly restricted to ventral
regions of the tegmentum; prominent in the substantia ni-
Brain Struct Funct (2007) 212:149–179
155
Q
U
OC1
RSC
RSCd
LP
ST
SC
AUD
Bv
SU
PO
OC1
PO
CA1
PAp
PAG
ECT
A
PAR
CLi
PH
VTA
PRC
ECT
MRF
MRF
ZI
RR
ECm
MB
TR
R
IP
EC
SUM
NP
V
OC2
RSC
OC
RSC
CA1
PRE
IC
DR
APN
TE
MRF
ECl
ECT
VTA
SNc
PRC
EC
SUM
S
RPO
MR
COA
W
OC1
RSC
OC
T
EC
AUD
CA1
SC
EC
DR
m
TE
MRF
PPT
MR
PRC
SUBv
VTA
IF
RPO
EC
T
X
OC2
OC1
RSC
SUBd
CA1
PAG
LC
NI
CLi
PRC
SNc
PN5
MRF
RPC
RM
EC
IP
Fig. 1 continued
gra-pars compacta (SNc) and ventral tegmental area
(VTA), but considerably less intense in the periaqueductal
gray (PAG) (Fig. 1q, r), the supramammillary nucleus
(SUM) and the central linear nucleus (CLi). There was a
progressive decline in VTA labeling, proceeding caudally.
Small numbers of labeled cells were observed in the posterior nucleus of thalamus (PO) and the mesencephalic
reticular formation (MRF) (Fig. 1q).
Cortically, at the level of the pons and medulla (Fig. 1u–
x), labeled cells were mainly localized to ECT and to the
lateral EC (ECl) with scattered labeling throughout RSC
and OC. Subcortically, the dorsal raphe nucleus (DR), the
pedunculopontine tegmental nucleus (PPT), and the locus
coeruleus (LC) were fairly densely labeled; CLi, the
median raphe nucleus (MR), and nucleus incertus (NI)
were lightly to moderately labeled (Fig. 1u–x). A few labeled neurons were seen in the pontine gray and pontine
reticular formation—nucleus pontis oralis (RPO) and
pontis caudalis (RPC) (Fig. 1w, x).
Afferents to the anterior cingulate cortex (AC)
At the site of injection (Fig. 3d) and rostral to it (Fig. 3a–c)
labeled cells were found along the medial wall of the mPFC
within FPm, the anterior PL, and medial orbital cortex (MO),
rostrally (Fig. 3a, b), and the AGm, AC, caudal PL, and IL,
caudally (Fig. 3c, d). Labeled cells spread to all layers of AC
(at and adjacent to the injection), but were mainly localized
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156
Brain Struct Funct (2007) 212:149–179
Fig. 2 Brightfield
photomicrographs depicting
retrogradely labeled neurons in
the basal forebrain (a, b), the
basolateral nucleus (BLA) of the
amygdala (c) and the midline
thalamus (d) produced by a FG
injection in AGm. Note: (a) at
low (a) and high (b) levels of
magnification, the presence of a
loosely distributed group of
labeled cells extending
dorsoventrally in the lateral
basal forebrain localized to the
acetylcholine containing cell
regions of the substantia
innominata and ventral
pallidum; (b) the presence of
labeled cells densely packed
within, and confined to, BLA of
amygdala (c); and (c) the
presence of labeled cells within
the ventral midline thalamus,
ventrally in nucleus reuniens
(RE) and dorsally in the
rhomboid nucleus (RH). Scale
bar for a = 1,000 lm; b,
c = 250 lm; d = 300 lm. See
list for abbreviations
to inner layers of PL and IL. Although labeling was stronger
ipsi- than contralateral to the injection, relatively significant
numbers of labeled neurons were visible contralaterally in
the mPFC. The VO and CLA were moderately to densely
labeled; AId was lightly labeled (Fig. 3a–d).
More caudally in the anterior forebrain (Fig. 3e–h), labeled cells were pronounced within the caudal AC,
dorsomedially, and CLA, ventrolaterally. Light to moderate numbers of labeled neurons were also present in AGm,
dorsal to AC, inner layers of AId, the dorsal taenia tecta
(TTd), and structures of the lateral BF: bed nucleus of stria
terminalis (BST), lateral preoptic area (LPO), MA, and SI.
At mid-levels of the forebrain (Fig. 3i–l), labeled cells
continued to be seen dorsomedially in the cortex, within
AC (Fig. 3i, j), extending caudally to the RSC. A few labeled cells were also present in motor cortices (AGm and
AGl) lateral to AC (Fig. 3k, l). Ventrolaterally, labeling
was virtually confined to CLA. As shown (Fig. 3j–l),
pronounced numbers of labeled neurons were observed
within the medial thalamus, mainly localized to PV, PT,
anteromedial (AM), IAM, lateral parts of MD, RH, CM,
123
and VM. The entire extent of AM was densely labeled,
particularly the ventral tier of AM (Fig. 3j, k). This is
depicted in the photomicrograph of Fig. 4a. Interestingly,
in contrast to heavy AM and IAM labeling, there was a
virtual absence of labeled neurons in the anterodorsal (AD)
and anteroventral (AV) nuclei of the anterior thalamus
(Fig. 3j–l).
Further caudally in the forebrain (Fig. 3m–p) labeled
cells were present in significant numbers in a region dorsal/
dorsolateral to the cingulum bundle (CB); that is, to AGm/
AGl, rostrally (Fig. 3m, n), and to RSC and the PAp
(Fig. 3o, p), caudally. The SSII, TE, ECT, and PRC were
moderately labeled. Subcortically, labeling was pronounced in the medial and intralaminar nuclei of thalamus
and in the basal nuclei of the amygdala, but was light
within the hypothalamus (Fig. 3m–p). Specifically, labeled
neurons were fairly densely concentrated within lateral
MD, CL, PC, IMD, RH, and RE of thalamus (Fig. 3m–o)
and in the basomedial (BMA) and BLA of amygdala
(Fig. 3m, n), but loosely (and lightly) dispersed in CM of
thalamus and PH, LHy, SUM, and the lateral mammillary
Brain Struct Funct (2007) 212:149–179
157
E
A
AGm
FPm
AGl
AC
PL
CP
FPl
VO
IL
LO
CLA
MO
ACC
AON
EN
AId
B
F
AGm
AGm
AC
PL
SSI
CP
VLO
AId
MO
VO
CLA
TTd
ACC
AId
OT
C
G
AGm
AGl
AC
AC
AGl
PL
IL
MS
VO
AId
CP
LS
CLA
DBh
VP
AIp
D
EN
H
AGm
SSI
AC
AC
CP
SF
IL
GP
BST
AId
CLA
PIR
SI
MA
LPO
PIR
Fig. 3 Series of representative rostro-caudally aligned schematic
transverse sections (a–x) depicting the location of retrogradely
labeled cells in the brain produced by a FG injection (d) in the
rostral anterior cingulate cortex (AC). One dot = one cell. Sections
modified from the rat atlas of Swanson (1998). See list for
abbreviations
nucleus (LM) of the hypothalamus. Figure 4c shows a
dense aggregate of labeled neurons in CL and the medially
adjacent lateral MD, dorsally, and significant but fewer
cells ventrally in PC of thalamus. Some labeled neurons
were also present in ZI (Fig. 3n) and PAG (Fig. 3p).
Cortically, at the level of the anterior midbrain (Fig. 3q–
t), labeled cells were abundant dorsomedially in RSC and
in the medial OC2 (Fig 3q, r) and ventrolaterally in PRC.
Scattered labeled cells were also found within TE, ECT,
lateral EC, and other parts of OC. Although labeling was
moderate in the ventral hippocampus (Fig. 3q–t), FG-reacted neurons were visible throughout CA1 of the ventral
hippocampal formation (HF) (Fig. 3r, s) and fairly densely
packed within the ventral subiculum (SUBv) (Fig. 3t). This
pattern of labeling is depicted in the photomicrograph of
Fig. 4b. Subcortically, labeling overall was fairly light;
strongest in SNc and VTA and less pronounced in PAG,
interpeduncular nucleus (IP) and CLi (Fig. 3q–t).
Cortically, at the level of the midbrain and pons
(Fig. 3u–x), labeled neurons were essentially restricted to
ECT and the entorhinal (ECl and ECm) cortices. Labeling
was densest in ECl (Fig. 3u, v). Labeling thinned subcortically (Fig. 3u–v), but was nonetheless visible in DR and
LC and to a much lesser degree in the MR, the laterodorsal
123
158
Brain Struct Funct (2007) 212:149–179
I
M
AGm
AGl
RSC
SSI
AC
SSI
CP
CL
PT
RT
PV
CLA
CM
RE
RH
PRC
LHy
SSII
PC
VB
SI
AIp
IMD
MD
RE
LA
BLA
LHy
BMA
J
N
RSC
RSC
AUD
LD
AV
RT
GI
AIp
PV
SSII
PT
AM
CL
MD
RE
CM
ECT
RE
ZI
AH
CEA
PRC
LA
BMA
PIR
K
SSp
O
PAp
RSC
RSC
AUD
PT
VB
VAL
IAM
RE
AM
AIp
LP
CL
CP
IMD
PF
CLA
ZI
LHy
PRC
CEA
LHy
PH
EC
COA
L
P
AGl
RSC
PAp
RSC
CA1
AUD
LP
AD
CP
MD
SSII
PAG
MRF
RH
VM
ZI
RE
VTA
ECT
CA
1
BL
A
LHy
EC
SUM
LM
PIR
Fig. 3 continued
tegmental nucleus (LDT), the lateral parabrachial nucleus
(PBl), and NI.
Afferents to the prelimbic cortex (PL)
As depicted (Fig. 5a–d), pronounced numbers of labeled
neurons were present in the PFC, mainly the medial PFC,
following a FG injection in PL. Labeling was predominantly localized to FPm, MO, VO, AGm, AC, PL (adjacent
to the injection and contralaterally), and IL, spreading
fairly evenly throughout all cortical layers of these regions.
The photomicrographs of Fig. 6a, b depict heavy labeling
contralaterally in anterior PL and MO, rostral to the
123
injection. Light to moderate numbers of labeled neurons
were present in VLO, CLA, AId, and AON (Fig. 5c, d).
More caudally in the anterior forebrain (Fig. 5e–h),
labeling remained pronounced within the mPFC, strongest in
AC, PL and IL, but was also dense in ventrolateral aspects of
the cortex particularly in the agranular insular cortex (AId
and AIv), CLA, and the endopiriform nucleus (EN). Figure 6c shows heavy concentrations of labeled cells in CLA
and AId, ipsilaterally. Additional labeled sites included the
TTd, and the LS (Fig. 5f, g). Labeling was considerably
stronger ipsi- than contralaterally in each of these structures.
At mid-levels of the anterior forebrain (Fig. 5i–l), labeling was restricted to dorsomedial and ventrolateral aspects of
Brain Struct Funct (2007) 212:149–179
159
Q
U
OC2
OC1
RSC
RSC
TE
IC
AUD
DR
m
EC
SC
APN
PAG
ECl
CA
1
MRF
VTA
SNc
PRC
RPO
MR
IP
NP
R
V
OC
EC
T
OC1
RSC
SUBd
CUN
AQ
PBl
EC
m
SC
CA1
TE
MRF
SNc
RN
VTA
IP
S
DR
ECT
RPO
MR
EC
RSC
W
OC1
OC
EC
T
IC
SUBd
PAp
EC
SC
m
CA1
PAG
MRF
LDT
CLi
DR
PRC
RR
RPC
SUBv
EC
IP
T
MR
X
RSC
ST
PO
LC
v
DG
SU B
TE
NI
RR
RPC
PN 5
ECT
MRF
RM
ECl
Fig. 3 continued
cortex, CLA, parts of the lateral BF and the midline thalamus. There was a virtual absence of labeled neurons in other
regions of cortex (e.g., primary motor, somatosensory, and
GI), the dorsal and ventral striatum, the medial BF, and the
hypothalamus (Fig. 5i–l). Cortical labeling was essentially
limited dorsomedially to AGm and AC, and ventrolaterally
to the posterior agranular insular cortex (AIp) (Fig. 5i–l).
Labeled cells were present throughout most of the anterior
midline thalamus—most heavily concentrated in PV, PT,
IAM, and RE (Fig. 5k, l). Within the BF, DBh and the LPO
were moderately labeled, while SI and the anterior LHy were
lightly labeled (Fig. 5i–l).
At the caudal forebrain, there was a dramatic reduction
in numbers of labeled neurons in the dorsomedial cortex,
particularly within RSC (Fig. 5m–p). As observed rostrally, however, labeled cells remained present on the lateral convexity of cortex, in AIp and CLA, rostrally, and
ECT, PRC and anterior EC, caudally (Fig. 5m–p). Subcortically, labeling was essentially restricted to the midline
thalamus and the basal nuclei of amygdala. Within the
thalamus, labeling was heavy in PV, MD (medial MD)
(Fig. 5m–p), RH and RE, but much less pronounced in
IAM, IMD, and CL of the intralaminar complex. As shown,
dense aggregates of labeled cells were present throughout
123
160
Brain Struct Funct (2007) 212:149–179
Fig. 4 Brightfield
photomicrographs depicting
retrogradely labeled neurons at
anterior (a) and posterior (c)
levels of the thalamus and
within the ventral hippocampus
(b) produced by a FG injection
in AC. Note: (1) the presence of
pronounced numbers of labeled
cells in the anteromedial
nucleus of thalamus (a) and
fewer numbers ventrally in
nucleus reuniens (a) and
dorsally in paratenial nucleus
(a) of thalamus; (2) the presence
of significant numbers of
labeled neurons in the lateral
mediodorsal nucleus (MD) and
the laterally adjacent central
lateral nucleus of thalamus (c)
as well as ventromedially in the
paracentral nucleus (c) but an
absence of labeling in the
medial and central MD; and (3)
the presence of moderate
numbers of labeled cells spread
dorsoventrally throughout CA1
of the ventral hippocampus (b).
Scale bar for a, b = 500 lm;
c = 300 lm. See list for
abbreviations
the extent of BLA (Figs. 5m–p, 7b). Light to moderate
numbers were also seen in BMA, the posterior (PA) and
anterior cortical nuclei (COA) of amygdala (Fig. 5o, p).
Cortically, at the level of the caudal diencephalon
(Fig. 5q–t), reacted cells were mainly restricted to the
parahippocampal cortices and HF; that is, moderate labeling in ECT, PRC and lateral EC, and dense labeling in CA1
of the ventral hippocampus extending dorso-ventrally
throughout CA1 of the ventral HF (Fig. 5s, t). The prominent CA1 labeling is depicted in the photomicrograph of
Fig. 7a. There was a noticeable absence of labeling in
remaining regions of the cortex, including RSC, PAp, and
OC (Fig. 5q–t). With the exception of fairly dense labeling
of BLA/BMA (Fig. 7c) as well as the amygdalo-piriform
transition zone (TR), subcortical labeling was confined to
relatively few structures. Lightly to moderately labeled
sites were PAG, VTA, PH, IP, SUM, and LM (Fig. 5q–t).
At the pons-medulla (Fig. 5u–x), labeling was essentially confined cortically to the ventral subiculum (Fig. 5u)
which was densely labeled, and ECl which was moderately
123
labeled. Subcortically, the DR was densely labeled; MR
and LC were moderately labeled (Fig. 5u–x).
Injections in other parts of PL resulted in the same
general pattern of labeling, but some differences in relative
densities of labeling. For instance, rostral (present case)
compared to caudal PL injections produced stronger cell
labeling in the CA1, BLA of amygdala, medial septum
(MS) and diagonal band nuclei and DR and MR of the
brainstem, while caudal injections gave rise to heavier
labeling in several regions of the BF including CLA, MA,
SI, and the VP.
Afferents to the infralimbic cortex (IL)
Similar to injections in dorsal regions of the mPFC, significant numbers of labeled cells were observed in anterior
regions of the forebrain (Fig. 8a–d) with IL injections
(Fig. 8d, e). Rostrally within mPFC, labeling extended
dorsoventrally throughout the mPFC to FPm, PL, and MO
(Fig. 8a, b), but caudally was mainly confined to the ven-
Brain Struct Funct (2007) 212:149–179
161
A
AGm
E
FPm
AC
AGl
FPl
PL
AON
MO
SSI
CLA
EN
IL
AId
TTv
B
PL
AGm
F
FPm
AC
FPl
CP
LO
CLA
VO
IL
ACC
EN
AId
AIv
C
AGm
G
AC
AGl
AC
SSI
IL
CP
PL
VLO
AId
CLA
GI
MO
AId
AON
D
EN
H
AGm
AGl
ACC
AC
SSI
AC
PL
AGm
CLA
CP
SSI
LS
IL
AId
CLA
ACC
AId
AIv
PIR
OT
Fig. 5 Series of representative rostro-caudally aligned schematic
transverse sections (a–x) depicting the location of retrogradely
labeled cells in the brain produced by a FG injection (c–e) in the
prelimbic cortex (PL). One dot = one cell. Sections modified from the
rat atlas of Swanson (1998). See list for abbreviations
tral mPFC (IL and PL) (Fig. 8c, d). Additional moderately
to heavily labeled sites were CLA, AId, and parts of AON
(Fig. 8b–d).
More caudally at the anterior forebrain (Fig. 8e–h), labeled cells were present in significant numbers in the
ventral mPFC (IL, PL, and TTd), CLA and AId/AIp.
Labeling outside of these areas was restricted to regions of
the BF; that is, to SI, DBh and the medial and LS. Of these
regions, labeling was densest in DBh. Some labeled neurons were also seen in the EN (Fig. 8g, h).
Mid-levels of the forebrain (Fig. 8i–l) were characterized by a marked reduction (from rostral levels) in numbers
of labeled neurons in the (neo) cortex. A few labeled cells
were present dorsomedially in AC, extending caudally to
RSC, but virtually none were seen in motor (AGm and
AGl) and somatosensory (SSI and SSII) cortices. Moderate
numbers were observed in CLA as well as ventrolaterally
in AIp, rostrally, and PRC, caudally (Fig. 8i–l). In contrast
with the cortex, labeling was pronounced throughout the
midline thalamus: heavy within PV, PT, medial MD, RH
123
162
Brain Struct Funct (2007) 212:149–179
I
M
AGl
RSC
SSI
AC
PV
LS
CP
SSII
IAM
CP
MS
RE
CLA
DBh
AIp
MD
VAL
RH
CLA
AIp
SI
CEA
LHy
EN
OT
PIR
J
BLA
N
AGm
RSC
AC
SSI
CP
SF
LD
SSII
MD
VAL
PV
GP
CM
CLA
SM
RH
VP
AIp
AIp
LPO
RE
MA
LHy
MPO
K
LA
BLA
PIR
O
AGl
RSC
SSI
AC
AUD
CP
PV
PV
MD
VB
RT
GI
SSII
AM
PT
GP
CM
RE
AIp
SI
AH
LHy
PRC
CEA
LA
EN
LHy
AA
PIR
RE
ZI
EC
BMA
BLA
L
P
RSC
PAp
RSC
SSI
CA1
AUD
LP
PV
CP
AV
SSII
RT
MD
AM
GP
RE
LHy
PO
TE
CM
PRC
PH
PA
BLA
CL
IMD
ZI
ECT
CLA
AIp
PV
PT
COA
BLA
BMA
Fig. 5 continued
and RE, moderate in IAM and light in CM (Fig. 8i–l).
Figure 9a shows a dense aggregate of labeled neurons
outlining the rostral RE. With the exception of a few labeled cells in the anterior hypothalamus (AH) and LHy,
there was notable absence at labeling within the hypothalamus at these levels (Fig. 8i–l).
More caudally in the forebrain (Fig. 8m–p), labeled
cells were largely confined to the midline thalamus and
medial hypothalamus, PRC, and the hippocampus. Similar
to rostral levels, the PV, medial MD, IMD, RH and RE
were densely labeled and CM lightly labeled. Labeling was
much more pronounced at the caudal than rostral hypothalamus, densest within the SUM (Figs. 8o, p, 9c). In
123
contrast with a general lack of labeling at the rostral
amygdala (Fig. 8i–l), significant numbers of labeled cells
were present in the caudal amygdala, heavily concentrated
in BLA and BMA and less so in COA and TR. A few
labeled cells were also found in the lateral nucleus of
amygdala (LA) (Fig. 8m). While some labeled neurons
were present rostrally in CA1 of the dorsal hippocampus
(Fig. 8o), numbers greatly increased at successively caudal
regions of the dorsal and particularly the ventral hippocampus (Fig. 8p).
Labeling was generally light within the cortex at the
midbrain (Fig. 8q–t); moderate numbers were observed in
ECT and PRC bordering the rhinal fissure, and far fewer in
Brain Struct Funct (2007) 212:149–179
163
Q
U
PAp
RSC
OC1
RSC
ST
PO
AUD
SC
LP
Bv
SU
PAG
PAG
MRF
ZI
ECT
VTA
MB
LM
SUM
BLA
ECT
CLi
RR
EC
m
CA1
EC
TE
MRF
ECl
IP
COA
NP
TR
R
V
OC2
OC1
RSC
CA1
E
PR
SC
AUD
LP
DR
MRF
TE
PAG
CA
1
PPT
PRC
PH
RPO
ECl
SUM
VTA
TR
MR
S
W
OC1
OC
RSC
IC
ECT
SC
PAG
NLL
SNc
RN
SUBv
m
EC
DR
CA1
MRF
RPO
PRC
SN
r
MR
ECl
VTA
T
X
OC2
RSC
SUBd
SC
TE
DG
CA1
LC
V4
MRF
PRC
VTA
RR
SUBv
ECl
RPC
RM
IP
Fig. 5 continued
RSC and ECl. As seen rostrally (Fig. 8p), dorsal and
ventral aspects of CA1 were densely labeled and merged to
form a continuous band of labeled cells, dorsoventrally in
CA1 (Fig. 8q–s). This is depicted in Fig. 10a. As with
CA1, labeled cells spread heavily throughout the extent of
the ventral subiculum (Figs. 8t, 10b). Subcortically, labeling was predominantly confined medially to the rostral and
central linear nuclei and to VTA (Fig. 8q–t). Some labeled
cells were present in the mesencephalic PAG, rostrally
(Fig. 8o, p) as well as caudally (Fig. 8t).
Labeling within the cortex at the level of the pons/medulla (Fig. 8u–x) was essentially confined to ECT and ECl.
A few labeled cells were also found scattered throughout
OC (Fig. 8u, v). Subcortically, labeling was prominent in
DR (Figs. 8u–w, 9b), in the isthmus region between DR
and MR (Fig. 8w), in LDT and in LC (Fig. 9d), moderate
in MR (Fig. 9c) and fairly light in the pontine central gray
and NI (Fig. 8x).
Similar to PL (see above), there were differences in
relative densities of labeling, but not overall patterns of
labeling with injections in different parts of IL. Specifically, denser labeling was observed in rostral parts of BLA
with rostral compared to caudal (above case) IL injections,
and considerably fewer labeled cells were seen in the
caudal midline thalamus (caudal PV and IMD) with
superficial (layers 1–3) relative to deep IL injections.
123
164
Brain Struct Funct (2007) 212:149–179
Fig. 6 Brightfield
photomicrographs depicting
retrogradely labeled neurons in
the contralateral prelimbic
cortex (a, b) and in the
claustrum (CLA) and the dorsal
agranular insular cortex (AId)
(c) produced by a FG injection
in PL. Note: (1) the presence at
low (a) and high (b) levels of
magnification of dense
aggregates of labeled cells in the
contralateral PL, spread
throughout all layers but most
heavily distributed in outer
layers 2/3 of PL; and (2) the
presence of pronounced
numbers of labeled neurons
throughout the anterior CLA (3)
and equally significant numbers
in AId, ventrolateral to CLA.
Scale bar for a = 750 lm;
b = 200 lm; c = 500 lm.
See list for abbreviations
Discussion
We examined afferent projections to the AGm, AC, PL,
and IL cortices in the rat. Each subdivision of the mPFC
receives a fairly unique set of afferent projections
(Figs. 11, 12). There were also common projections to the
four divisions of the mPFC. These included afferents from
adjacent regions of the mPFC, the insular and entorhinal
cortices, CLA, CA1/subiculum of hippocampus, basal nu-
123
clei of the amygdala, midline thalamus, VTA, DR, and LC
(Figs. 11, 12).
Brief summary and comparisons of main afferents
to AGm, AC, PL, and IL
The primary sources of afferents projections to the four
divisions of the mPFC are summarized in Figs. 11 and 12.
As depicted, the AGm receives widespread input from
Brain Struct Funct (2007) 212:149–179
165
Fig. 7 Brightfield
photomicrographs depicting
retrogradely labeled neurons in
CA1and the dorsal and ventral
subiculum of the ventral
hippocampus (a) and rostral (b)
and caudal (c) levels of the
amygdala produced by a FG
injection in PL. Note: (1) the
presence of pronounced cell
labeling throughout the extent
of the ventral hippocampus,
from the dorsal subiculum
through CA1 to the ventral
subiculum (a); (2) the presence
of labeled neurons, confined to,
and distributed throughout the
anterior basolateral nucleus of
amygdala (BLA); and (3) the
presence of labeled cells
caudally in the amygdala,
mediolaterally spanning the
posterior part of the basomedial
nucleus (BMAp), posterior BLA
and the amygdalo-piriform
transition zone (TR). Scale bar
for a = 1,100 lm; b = 500 lm;
c = 750 lm. See list for
abbreviations
non-limbic and limbic regions of the cortex as well as
from specific (relay) and ‘non-specific’ nuclei of the
thalamus. In like manner, AC receives afferents from
diverse regions of cortex, but less dense from non-limbic
cortex and more restricted from limbic cortex than those
to AGm (Fig. 11b). There is a considerable overlap in
thalamic projections to AGm and AC, with the notable
exception that the anterior medial nucleus of thalamus
distributes densely to AC. There is a dramatic shift in
cortical and thalamic projections to the ventral (PL and
IL) compared to the dorsal (AGm and AC) mPFC, such
that major inputs to ventral mPFC predominantly originate from limbic cortices and from the midline thalamus.
All regions of the mPFC receive complementary (overlapping) projections from the BF, amygdala, hypothalamus and brainstem (Figs. 11, 12), with some important
differences among divisions. For example, regions of the
lateral BF primarily target AGm/AC, while the medial BF
targets PL/IL, and the amygdala distributes more heavily
to the ventral than to the dorsal mPFC. Overall hypothalamic projections to the mPFC are light, with the
exception of relatively pronounced projections from the
SUM to IL. Finally, the VTA and the DR distribute
significantly to all divisions of the mPFC.
Afferents to the four divisions of the mPFC:
comparisons with previous studies and functional
implications
Medial agranular cortex
The main sources of input to AGm were from the cortex
and thalamus. Extra-thalamic subcortical afferents to AGm
were moderate and less pronounced than to other divisions
of the mPFC.
The AGm of rats is also termed the medial precentral
area (or Fr2 region of Zilles 1985) and is partially coextensive with the secondary motor cortex (Zilles and Wree
1995; Gabbott et al. 2005). In an early examination of
cortical connections of AGm, Reep et al. (1990) described
diverse cortical inputs to AGm from the cortex FPm, the
medial and ventrolateral orbital cortices, AGl (or primary
motor cortex), insular cortex (INC), SSI and SSII, RSC,
auditory and occipital cortices. Based on ‘extensive cortico-cortical connections,’ Reep et al. (1990) proposed that
AGm is a multimodal association area with direct actions
on motor systems, and accordingly serves a central role in
directed spatial attention. Supporting this, lesions of AGm
in rats produce contralateral neglect (failure to attend to
123
166
Brain Struct Funct (2007) 212:149–179
AGm
E
A
FPm
PL
SSI
PL
FPl
CP
IL
CLA
LO
MO
ACC
EN
AId
B
F
FPm
AGm
AGl
SSI
AC
AC
CLA
TTd
CP
CLA
MO
AId
LS
ACC
AON
OT
C
AGm
G
AGm
SSI
AC
AGl
PL
LS
CP
CLA
MS
IL
SSII
GI
AId
DBh
SI
AIp
D
AGl
H
AC
AGl
AC
CP
SF
CLA
SSII
IL
GP
ACC
CLA
AId
PIR
MPO
AIp
MA
DBh
LPO
VP
EN
Fig. 8 Series of representative rostro-caudally aligned schematic
transverse sections (a–x) depicting the location of retrogradely
labeled cells in the brain produced by a FG injection (d, e) in the
infralimbic cortex (IL). One dot = one cell. Sections modified from
the rat atlas of Swanson (1998). See list for abbreviations
meaningful stimuli presented contralaterally), comparable
to deficits seen with lesions/damage to Brodmann’s area 8
of primates (Crowne and Pathria 1982; Corwin et al. 1986;
King and Corwin 1993).
We described a pattern of cortical projections to AGm
largely consistent with that shown by Reep et al. (1984,
1990) as well as others (van Eden et al. 1992; Conde et al.
1995; Heidbreder and Groenewegen 2003), with some
important differences. Specifically, we demonstrated considerably stronger projections from FPm, agranular insular
cortex and PRC to AGm than reported previously (Reep
et al. 1990), but less pronounced projections from RSC and
occipital cortex. These differences could involve relative
size and placements of injections across reports.
With respect to the thalamus, it is well established that
MD represents a major input to AGm—as well as to other
subdivisions of the mPFC. In fact, the mPFC of non-primates has been described as MD projection cortex (Leonard 1969; Uylings and van Eden 1990). In accord with
several previous reports (Krettek and Price 1977; Groenewegen 1988; Conde et al. 1990; Ray and Price 1992;
Hicks and Huerta 1991; Reep and Corwin 1999), we found
that AGm receives pronounced projections from the lateral
MD. Other prominent sources of thalamic afferents to
123
Brain Struct Funct (2007) 212:149–179
I
167
M
AGl
RSC
AC
SSII
CP
SSII
PV
VB
GP
RE
GI
SI
AIp
AH
IMD
MD
AM
PT
TE
CLA
LHy
CM
RH
RE
BLA
PIR
J
PRC
LA
BLA
CEA
PIR
N
AGm
PAp
RSC
SSI
AUD
FI
PV
LP
PV
AV
MD
VAL
AM
IAM
GI
IMD
RH
RE
ECT
LHy
ZI
CM
AIp
PH
CEA
LHy
PA
BMA
PIR
K
O
AGl
PAp
BLA
RSC
RSC
SSI
CA1
AUD
LP
MD
VAL
VM
IAM
RH
MRF
CLA
TE
RE
ECT
ZI
PH
mM
PRC
LHy
S
US U
m
M
CEA
PAG
EC
MB
BL
AIp
PV
A
CP
SUM
BLA
COA
PIR
L
P
OC2
TR
1
RSC
RSC
CA1
PAp
PV
SC
CA3
LD
MD
VB
SSII
CM
GI
AUD
VTA
RH
RE
PRC
A
ME
BLA
SNc
EC
SUBv
SUM
COA
TR
LHy
Fig. 8 continued
AGm include the CL, PC, CM, posterior (PO), VAL, and
VM nuclei of thalamus (Herkenham 1979; Conde et al.
1990; Hicks and Huerta 1991; Reep and Corwin 1999,
present results). Reep and Corwin (1999) reported that
afferents to successively more caudal regions of AGm
originate from more caudal and lateral parts of the thalamus. Consistent with this, Hicks and Huerta (1991) described projections from the lateral dorsal (LD) and LP
nuclei of thalamus to the caudal but not to the rostral AGm,
and we found that injections in the rostral AGm gave rise to
few labeled cells in LD or LP. Hicks and Huerta (1991)
proposed that visuomotor thalamic input (LD/LP) to the
caudal AGm supports a role for this area in visuomotor
functions.
In addition to prominent afferents from somatomotor/
visuomotor regions of thalamus to AGm, some reports
(Conde et al. 1990; Hicks and Huerta 1991; Vertes et al.
2006), but not others (Reep and Corwin 1999), have
demonstrated significant input to AGm from the midline
thalamus. We described projections from the PV, PT, IAM,
IMD, CM, rhomboid (RH) and reuniens (RE) nuclei of the
midline thalamus to AGm, most heavily from RH and RE.
The latter is consistent with our recent demonstration
(Vertes et al. 2006), using anterograde tracers, of pronounced RH and RE projections to AGm, mainly to layers
1 and 5/6. Other studies have similarly described IAM,
CM, RH, and RE projections to AGm (Conde et al. 1990;
Hicks and Huerta 1991).
123
168
Brain Struct Funct (2007) 212:149–179
Q
U
OC1
RSC
RSC
E
PR
SUBd
ECT
CA1
PA
R
SC
MRF
RLi
SNc
DR
NLL
ECT
EC
m
PPT
MR
VTA
IF
TE
IC
AUD
EC
SUBv
NP
R
V
OC2
OC1
RSC
RSC
IC
AUD
ECT
PAG
DR
EC
MG
CA1
SC
RN
PRC
VTA
r
SN
SUBv
S
m
MRF
ECl
CUN
MR
EC
RPO
IP
W
OC1
OC2
RSC
EC
IC
T
CA1
SC
EC
m
SUBd
TE
MRF
DR
PB
ECT
LDT
VTA
RPO
SNc
T
MR
ECl
SUBv
OC1
X
RSC
PO
ST
SC
Bv
SU
PAG
ECT
LDT
CLi
m
EC
RR
NI
RPC
IP
NP
Fig. 8 continued
Other inputs to AGm
In addition to thalamus and cortex, other prominent sources
of afferents to AGm were from CLA, cholinergic cell
groups of the BF, basolateral nucleus of amygdala (BLA),
SNc/VTA and monoaminergic nuclei of the brainstem.
As well recognized, the CLA is reciprocally linked to
virtually all areas of the cortex, including mPFC (Markowitsch et al. 1984; Sloniewski et al. 1986; Sherk 1988;
Witter et al. 1988; Kowianski et al. 1998; Majak et al.
2000; Zhang et al. 2001). Using anterograde tracers, Zhang
et al. (2001) showed that CLA mainly targets AGm of the
123
mPFC. Consistent with this, retrograde injections in the
dorsal mPFC were shown to produce dense cell labeling in
CLA (Hur and Zaborszky 2005). CLA appears to represent
a hub for intracortical communication (Edelstein and Denaro 2004).
Similar to CLA, ACh-containing cells of the BF project
widely throughout the cortex (Bigl et al. 1982; Rye et al.
1984; Saper 1984; Woolf et al. 1984; Luiten et al. 1987;
Woolf 1991; Gritti et al. 1997), and more densely to limbic
than to non-limbic regions of cortex (Bigl et al. 1982;
Woolf et al. 1984; Woolf 1991). The present location of
labeled cells of the BF (SI/VP) corresponds to sites of
Brain Struct Funct (2007) 212:149–179
169
Fig. 9 Brightfield
photomicrographs depicting
retrogradely labeled neurons in
the midline thalamus (a), the
dorsal (DR) and median raphe
(MR) nuclei (b), the
supramammillary nucleus
(SUM) (c) and the locus
coeruleus (LC) (d) produced by
a FG injection in IL. Note the
presence of a dense aggregate of
labeled cells ipsilateral (to the
IL injection) within nucleus
reuniens of the rostral ventral
midline thalamus as well as
dense cell labeling in DR, MR,
SUM, and LC. Scale bar for
a = 130 lm; b, c = 300 lm;
d = 350 lm. See list for
abbreviations
Fig. 10 Brightfield
photomicrographs depicting
retrogradely labeled neurons at
a rostral (a) and caudal (b) level
of the ventral hippocampus
produced by a FG injection in
IL. Note the presence massive
cell labeling throughout the
extent of CA1 and the
subiculum, rostrally (a) and the
ventral subiculum, caudally (b).
Scale bar for a, b = 1,000 lm.
See list for abbreviations
123
170
Fig. 11 Summary of main
sources of afferent projections
to AGm (a) and AC (b) from the
cortex (non-limbic and
‘limbic’), basal forebrain,
amygdala, thalamus,
hypothalamus, midbrain, and
pons/medulla. Red, green, and
blue represents heavy,
moderate, and light projections,
respectively, to AGm and AC.
Non-limbic cortex is defined as
motor, somatosensory, special
sensory, and associational
regions of cortex, while ‘limbic’
cortex is defined as remaining
regions of cortex including
orbital cortices and the
hippocampal formation. See list
for abbreviations
Brain Struct Funct (2007) 212:149–179
A
Non-Limbic
Cortex
FPm
AGm
SSI
SSII
OC2
RSC
AGl
GI
AUD
PAp
OC1
TE
Limbic
Cortex
Basal
Forbrain
CLA
MO
VO
VLO
AC
PL
AId
AIp
PRC
DBh
SI
MA
GP
VP
Thalamus
CL
MD
CM
PV
RH
RE
VM
PT
heavy labeling
moderate labeling
light labeling
AM
IAM
IMD
PC
VAL
IL
ECT
EC
CA1
LO
LP
AGm
Amygdala
BLA
BMA
MEA
PA
TR
Hypothalamus
LHy
PH
Midbrain
Pons/medulla
VTA
DR
PPT
LC
SNc
PAG
SUM
CLi
ZI
SUM
MRF
IP
MR
NI
RPO
RPC
B
Non-Limbic
Cortex
AGm
PAp
RSC
OC2
FPm
AUD
AGl
GI
TE
SSII
Limbic
Cortex
Basal
Forbrain
CLA
AC
PL
SI
TTd
IL
MO
VO
PRC
EC
CA1
BST
DBh
LPO
MA
AIp
ECT
Thalamus
AM
CL
RE
RH
IAM
MD
PC
CL
CM
IMD
PV
PC
VM
PT
AC
Amygdala
BLA
BMA
Hypothalamus
LHy
PAG
PH
SUM
LM
anterograde BF injections (Luiten et al. 1987) that gave rise
to significant labeling of mPFC, particularly within AGm
(see their Fig. 6, p. 240). Cholinergic projections to cortex
reportedly serve important roles in behavioral/EEG arousal
and attentional mechanisms (Woolf 1991; Nunez 1996;
Jimenez-Capdeville et al. 1997; Zaborszky et al. 1999;
Cape et al. 2000; Zaborszky 2002; Jones 2004; Sarter et al.
2005). It worth noting, however, that the ACh region of
BF, contains other types of neurons, prominently including
GABAergic and glutamatergic cells, that project to most of
the cortical sites as ACh neurons (Brashear et al. 1986;
123
Midbrain
Pons/medulla
VTA
DR
SNc
IP
CLi
LC
NI
LDT
MR
PB
Zaborszky et al. 1986; Gritti et al. 1997, 2003; Zaborszky
2002).
Although earlier reports have described projections from
the (BLA) to mPFC (Kita and Kitai 1990; McDonald 1987,
1991; Bacon et al. 1996; Gabbott et al. 2006), those to
AGm appear to be considerably less pronounced than
shown here. Evidence suggests that BLA to mPFC projections (particularly to IL/PL) convey information on the
emotional properties of sensory stimuli (Garcia et al. 1999;
LeDoux 2000; Pare et al. 2004; Gabbott et al. 2006; Vertes
2006), involved in executive functions of the mPFC
Brain Struct Funct (2007) 212:149–179
Fig. 12 Summary of main
sources of afferent projections
to PL (a) and IL (b) from the
cortex (non-limbic and
‘limbic’), basal forebrain,
amygdala, thalamus,
hypothalamus, midbrain, and
pons/medulla. Red, green, and
blue represents heavy,
moderate, and light projections,
respectively, to PL and IL. Nonlimbic cortex is defined as
motor, somatosensory, special
sensory, and associational
regions of cortex, while ‘limbic’
cortex is defined as remaining
regions of cortex including
orbital cortices and the
hippocampal formation. See list
for abbreviations
171
A
Non-Limbic
Cortex
FPm
AGm
RSC
Basal
Forbrain
Limbic
Cortex
CLA
MO
VO
AC
PL
IL
AId
AIv
AIp
CA1
SUB
PRC
TTd
DBh
LPO
EN
VP
Thalamus
PT
PV
MD
RE
RH
heavy labeling
IMD
IAM
light labeling
moderate labeling
CL
EC
ECT
PL
Amygdala
BLA
BMA
TR
PA
COA
Hypothalamus
Midbrain
Pons/medulla
SUM
VTA
DR
LM
LHy
PH
PAG
IP
SNc
LC
MR
B
Non-Limbic
Cortex
FPm
RSC
Basal
Forbrain
Limbic
Cortex
DBh
CLA
IL
CA1
SUB
TTd
EN
PL
AIp
PRC
EC
MS
LS
MPO
SI
AC
ECT
Thalamus
RE
RH
PT
PV
MD
IAM
IMD
CM
IL
Amygdala
Hypothalamus
Midbrain
Pons/medulla
BLA
BMA
TR
SUM
VTA
CLi
DR
LDT
PAG
SNc
MR
LC
COA
LA
PA
(Salinas et al. 1993; Balleine et al. 2003; Pare 2003;
Floresco and Ghods-Sharifi 2007).
Anterior cingulate cortex
Similar to AGm, the main sources of afferents to the
anterior AC were from regions of cortex and the thalamus.
As discussed below, however, cortical input to AC differs
from that to AGm. The primary sources of cortical afferents to AC were from FPm, other regions of mPFC (mainly
from AC and dorsal PL), PAp, RSC, PRC, entorhinal and
secondary visual cortices, as well as CA1/subiculum of HF.
Projections were strongest from AC, PAp, and RSC.
LHy
AH
PAG
NI
RPO
In an examination of cortical afferents to AGm, Reep
et al. (1990) made control injections in AC. In general
accord with present findings, they described afferents to
AC from AGm, various regions of RSC, and from
primary and secondary visual cortices, but failed to
identify them from PAp, parahippocampal cortices (PRC
and EC) and HF. These differences likely involve the
fact that our injections were mainly rostral, theirs caudal,
in AC.
In a recent comprehensive examination of intrinsic AC
connections, Jones et al. (2005) reported that: (1) the rostral
one third of AC is primarily connected with IL, PL and
itself (rostral AC); (2) dorsal and ventral zones of the
123
172
caudal two-thirds of AC are extensively interconnected;
and (3) the caudal RSC projects to the rostral ACm, while
the rostral RSC projects to the caudal AC. The latter
findings are consistent with present and previous results
(van Groen and Wyss 1990a, 1992, 2003; Risold et al.
1997; Shibata et al. 2004) showing that RSC strongly targets AC. Based on extensive RSC connections with AC,
and additionally with parts of the limbic thalamus, subiculum/postsubiculum, and occipital cortex, van Groen and
Wyss (2003) proposed that RSC is a focal point for the
integration of limbic information. As they noted, RSC is an
essential component of Papez’s circuit (Papez 1937) and
RSC lesions produce marked deficits in spatial navigation
and memory (Sutherland et al. 1988; Cooper and Mizumori
2001; Vann and Aggleton 2002).
The PAp is a large area, bordered rostrally by the
hindlimb sensorimotor cortex, caudally by primary/secondary visual cortices, medially by RSC and laterally by
SSI (Corwin and Reep 1998; Swanson 1998). Reep and
colleagues (Reep et al. 1990, 1994, 2003; Corwin and Reep
1998; Cheatwood et al. 2005) have described an extended
circuitry involving the medial PAp, AGm, Oc2M, VLO
and the dorsocentral striatum that participates in directed
spatial attention, and when disrupted, produces spatial neglect (Corwin et al. 1986; Crowne et al. 1986; King et al.
1989; King and Corwin 1993; Van Vleet et al. 2003).
In addition to afferents from orbital, mPFC and visual
cortices (and associated thalamic nuclei), PAp receives
input from somatosensory and auditory regions of cortex
(Chandler et al. 1992; Reep et al. 1994). In this respect,
PAp, like RSC, is a mulitmodal integration zone. In accord
with earlier reports (Reep et al. 1990; Corwin and Reep
1998), we described strong PAp to AGm projections, but
also observed equally dense medial PAp projections to AC.
This projection does not seem to have been reported previously.
As indicated, there is a progressive increase in the
strength of hippocampal and parahippocampal projections
from the dorsal to the ventral mPFC. Similar to AGm,
parahippocampal afferents to AC were shown to primarily
originate from PRC and lateral EC and to a much lesser
degree from the ectorhinal cortex (ECT). This is consistent
with the findings of several earlier reports (Swanson and
Kohler 1986; Insausti et al. 1997; Delatour and Witter
2002). While previous studies have demonstrated projections from the hippocampus (CA1/subiculum) to the ventral mPFC (IL/PL) (Swanson 1981; Irle and Markowitsch
1982; Ferino et al. 1987; Jay et al. 1989; van Groen and
Wyss 1990b; Jay and Witter 1991; Carr and Sesack 1996),
this is the first report to describe them to the dorsal mPFC:
moderate to AC and light to AGm.
In general accord with previous reports, we showed that
afferents to AC from ‘relay’ nuclei of thalamus arise from
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Brain Struct Funct (2007) 212:149–179
mid-lateral regions of the thalamus. This involves projections from lateral MD, VAL (lightly), VM, CL, PC, and
anteromedial (AM) nuclei of thalamus. Conde et al. (1990)
described similar findings, but also projections (not seen
here) from PO and LD of thalamus. The conflicting results
could involve the (partial) inclusion of AGm in their AC
injections (Conde et al. 1990, 1995).
In accord with present findings, van Groen et al. (1999)
described massive AM projections to AC, mainly originating from the ventromedial AM. As has been demonstrated (Sripanidkulchai and Wyss 1986; Shibata and Kato
1993; van Groen et al. 1999), there are marked differences in projections from the anterior thalamus to the
anterior and posterior AC (or RSC), such that AM distributes selectively to AC and AV/AD to RSC. While
earlier reports described (at best) modest projections from
the midline thalamus to AC (Conde et al. 1990, 1995), we
showed that several nuclei of the midline thalamus,
including PV, PT, IAM, CM, RH, and RE, distribute
significantly to AC. RE/RH projections to AC have recently been demonstrated using anterograde tracers
(Vertes et al. 2006).
Other inputs to AC
Similar to AGm, AC receives input from several (nonthalamic) subcortical sites including the CLA, TTd, MA,
SI, BST of the BF, the BLA/BMA of amygdala, the posterior nucleus (PH) of hypothalamus, the mesencephalic
PAG, SNc and VTA of the midbrain, and monoaminergic
groups of the brainstem. This is consistent with the findings
of several previous reports of diverse subcortical forebrain
(Bigl et al. 1982; Markowitsch et al. 1984; Rye et al. 1984;
Saper 1984; Woolf et al. 1984; Sloniewski et al. 1986;
Luiten et al. 1987; McDonald 1987, 1991; Sherk 1988;
Witter et al. 1988; Woolf 1991; Vertes et al. 1995; Bacon
et al. 1996; Gritti et al. 1997; Kowianski et al. 1998; Majak
et al. 2000; Zhang et al. 2001; Dong and Swanson 2006a, b;
Gabbott et al. 2006) and brainstem inputs to AC (Swanson
1982; Foote et al. 1983; Waterhouse et al. 1983; Vertes and
Martin 1988; Herrero et al. 1991a; Vertes 1991; Cameron
et al. 1995; Morin and Meyer-Bernstein 1999; Vertes et al.
1999; Carr and Sesack 2000a, b; Berridge and Waterhouse
2003).
Regarding VTA and SNc, it is well documented that
VTA is a major source of projections to the mPFC (for
review, Seamans and Yang 2004), but projections from
SNc to mPFC are less well established. In support of
present findings, however, others have demonstrated
moderate SNc projections to the mPFC (Loughlin and
Fallon 1984; Conde et al. 1995) and, like here, have shown
that they predominately originate from medial parts of SNc
and distribute to the dorsal and ventral mPFC.
Brain Struct Funct (2007) 212:149–179
Prelimbic cortex
Probably the most significant change in the distribution of
afferents to PL (and IL) from those to AGm/AC was a
progressive decline in cortical afferents to the ventral
mPFC. Specifically, there was a marked reduction in
cortical projections, mainly involving sensory (special
sensory and somatosensory), motor or associational regions (RSC and PAp) of cortex, to the ventral as compared to the dorsal mPFC.
With respect to cortical input, however, PL nonetheless
receives projections from several regions of cortex
including FPm, anterior PL, medial (MO) and VO, IL,
dorsal and (rostral) posterior agranular insular, perirhinal
and entorhinal cortices. In addition, the CA1/subiculum
distributes densely to PL—much heavier than to AC or
AGm. These findings are consistent with previous demonstrations of significant orbital and limbic cortical afferents to PL (Reep and Winans 1982; Swanson and Kohler
1986; Jay et al. 1989; Hurley et al. 1991; Jay and Witter
1991; Yasui et al. 1991; Insausti et al. 1997; Shi and
Cassell 1998; Delatour and Witter 2002; Gabbott et al.
2003; Jasmin et al. 2004; Vertes 2004).
The insular cortex (INC) interconnects with the ventral
mPFC (PL and IL) in a topographically organized manner
(Allen et al. 1991; Yasui et al. 1991; Shi and Cassell 1998;
Gabbott et al. 2003; Jasmin et al. 2004, present results). For
instance, we showed that the rostral INC (mainly AId) primarily targets PL and the caudal INC (mainly AIp) targets
IL. Consistent with this, Gabbott et al. (2003) demonstrated
that: (1) AId primarily projects to PL and dysgranular
insular (DI)/AIp mainly to IL; (2) AIv and the GI distribute
lightly to IL/PL; and (3) AId fibers to PL mainly terminate
in layers 2/3 and form asymmetric connections with
dendritic spines of PL cells. In a complementary manner,
there are strong (and selective) return projections from PL to
AId, and from IL to AIp (Sesack et al. 1989; Hurley et al.
1991; Gabbott et al. 2003; Vertes 2004).
Supporting present findings, several reports have demonstrated massive hippocampal projections (CA1/subiculum) to PL (Swanson 1981; Irle and Markowitsch 1982;
Ferino et al. 1987; Jay et al. 1989; van Groen and Wyss
1990b; Jay and Witter 1991; Carr and Sesack 1996). In
contrast, however, with earlier reports (Ferino et al. 1987;
Jay et al. 1989), we showed stronger CA1/subicular projections to IL than to PL. Interestingly, despite strong HF to
mPFC projections, there are no direct return projections
from the mPFC to the hippocampus (Beckstead 1979;
Room et al. 1985; Sesack et al. 1989; Hurley et al. 1991;
Takagishi and Chiba 1991; Vertes 2004). In the absence of
such projections, we have suggested (Vertes 2002, 2004,
2006; Vertes et al. 2007) that the RE of the midline thalamus is an important relay in the transfer of information
173
from the mPFC to the hippocampus (Wouterlood et al.
1990; Bokor et al. 2002). For instance, we demonstrated
that all divisions of the mPFC distribute heavily to RE
(Vertes 2002; McKenna and Vertes 2004), and RE in turn
is the source of pronounced projections to HF (CA1/subiculum) (Vertes et al. 2006, 2007).
Thalamic afferents to PL originate almost entirely from
the midline thalamus and MD. Of the midline groups, the
PT, PV, IAM, CM, rhomboid, and reuniens nuclei distribute densely to PL. Previous reports using anterograde or
retrograde tracers have described similar findings (Herkenham 1978; Ohtake and Yamada 1989; Berendse and
Groenewegen 1991; Conde et al. 1995; Moga et al. 1995;
Risold et al. 1997; Van der Werf et al. 2002; Vertes et al.
2006). We recently demonstrated that RE and RH distribute throughout the mPFC, terminating heavily in IL/PL,
mainly within layers 1 and 5/6 of these regions (Vertes
et al. 2006). It has been suggested that midline thalamic
input to the mPFC (and other parts of limbic cortex) participate in processes of arousal and attention (Van der Werf
et al. 2002) and/or serve to gate the flow of information to
and among limbic forebrain structures (Vertes 2006; Vertes
et al. 2006).
Other inputs to PL
We recently reviewed evidence indicating that IL and PL
of rats serve separate and distinct functions (Vertes 2006).
IL is primarily involved in affective/visceromotor functions, homologous to the orbitomedial PFC of primates,
while PL (and ventral AC) participates in cognitive/limbic
functions homologous to the lateral/dorsolateral cortex of
primates. Associated with its role in cognition, PL distributes to a relatively small groups of structures that
subserve cognition and have been designated the ‘PL circuit’ (Alexander et al. 1990; Groenewegen et al. 1990).
They mainly include the insular cortex (AId), the hippocampus (via RE), CLA, ACC, BLA, MD, RE, and VTA.
Lesions of each of these structures, like those of PL, produce deficits in delayed response tasks and memory (Harrison and Mair 1996; Seamans et al. 1998; Floresco et al.
1999; Romanides et al. 1999; Kalivas et al. 2001; Barros
et al. 2002; Pare 2003; Roozendaal et al. 2004; Seamans
and Yang 2004; Cain et al. 2006).
As demonstrated here, PL receives input from each of its
major targets including AId, HF, CLA, ACC (via VP and
MD), RE, and VTA. Dopaminergic VTA afferents to PL
(and mPFC) have been extensively examined (Seamans
and Yang 2004) and appear to play a critical role in PLassociated behaviors. Using a disconnection procedure
wherein the VTA and HF were temporarily disrupted on
opposite sides of the brain, Seamans et al. (1998) showed
that the simultaneous blockade of hippocampal inputs to
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174
PL and dopamine (D1) receptors at PL disrupted performance on delayed, but not on non-delayed, versions of the
the radial arm maze (RAM) task. Regarding the possible
role of dopamine in hippocampal-prefrontal interactions,
Seamans et al. (1998) suggested that: ‘D1 receptors in the
PFC may modulate the transfer of spatial information from
the hippocampus to the PFC at a time when a prospective
series of response must be organized and executed.’
Infralimbic cortex
By comparison with other subdivisions of the mPFC, IL
receives considerably fewer inputs from adjacent regions
of the mPFC. Within the mPFC, PL is the main source of
afferents to IL. In a similar manner, cortical inputs to IL are
essentially limited to PL, AId, HF, and parahippocampal
structures. There is a virtual absence of projections from
sensorimotor, special sensory or associational regions of
cortex to IL.
Insular cortical projections to IL primarily originate
from AIp and to a much lesser extent from the dysgranular
INC, dorsal to AIp. Consistent with this, using anterograde
tracers, Shi and Cassell (1998) demonstrated that AIp
selectively targets IL of mPFC. AIp receives convergent
visceral and limbic input (Saper 1982; Ruggiero et al.
1987; Allen et al. 1991), and reportedly represents a major
source of viscerosensory information to the visceromotor
cortex—or IL.
Despite limited (neo/allo) cortical input to IL, the hippocampus (CA1/subiculum) distributes massively to IL. If,
as indicated, IL represents a visceromotor center, hippocampal projections to IL may serve to associate past events
(including their affective quality) to present ones for
impending actions. In this regard, a characteristic feature of
bilateral damage to the ventromedial prefrontal cortex in
humans is a pervasive blunted affect (hypoemotionality)
coupled with generally inappropriate and often strongly
negative emotional reactions to relatively minor frustrations (Damasio et al. 1990; Barrash et al. 2000; Berlin et al.
2004; Anderson et al. 2006; Koenigs and Tranel 2007).
Related to the foregoing, Mayberg et al. (2005) recently
demonstrated that deep brain stimulation localized to IL
(presumably suppressing IL activity) produced a marked
remission of depression in human subjects.
Thalamic afferents to IL largely originate from the same
midline thalamic groups that project to PL. They primarily
include medial MD, PV, PT, IAM, RH, and RE. Only
minor differences were observed in projections to IL and
PL. Compared with PL, cells projecting to IL were directly
aligned along the midline (particularly in MD), and CM
distributes much less densely to IL than to PL.
As a putative visceromotor center, IL receives visceral
afferent information from the INC (AIp). There are rela-
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Brain Struct Funct (2007) 212:149–179
tively few additional sources of visceral/limbic input to IL
(or to the mPFC). They include the LS and horizontal
nucleus of the diagonal band (DBh) of the BF, the basolateral (BLA) and TR of amygdala, and the SUM of the
hypothalamus. In contrast, the midline thalamus, particularly the ventral midline thalamus, receives widespread
‘limbic’ afferents from diverse structures of the BF,
amygdala, hypothalamus and brainstem (Cornwall and
Phillipson 1988; Chen and Su 1990; Risold et al. 1997;
Krout et al. 2002; Van der Werf et al. 2002; McKenna and
Vertes 2004). These findings, coupled with the demonstration that the midline thalamus projects heavily to IL
(and to PL), suggest that midline thalamus is a primary
route by which limbic information reaches the mPFC
(Vertes 2006).
Other inputs to IL
Although IL receives fewer overall inputs than do other
divisions of mPFC, it is nonetheless the target of some
subcortical limbic structures that do not project elsewhere
in the mPFC—or certainly to the same degree as to IL.
These include the LS, DBh, BLA, TR, LHy, SUM, VTA,
PAG, DR, MR, NI, and the LDT. This is consistent with
previous demonstrations of relatively substantial projections from these sites to IL (Swanson 1982; Rye et al. 1984;
McDonald 1987, 1991; Bacon et al. 1996; Herrero et al.
1991a, b; Vertes 1991, 1992; Cameron et al. 1995; Morin
and Meyer-Bernstein 1999; Vertes et al. 1999; Carr and
Sesack 2000a, b; Goto et al. 2001; Olucha-Bordonau et al.
2003; Gabbott et al. 2006). Regarding LDT, it is well
recognized that LDT is a major source of cholinergic
afferents to the thalamus and parts of the BF (Hallanger
and Wainer 1988), but direct LDT projections to the cortex
(or to mPFC) are not well documented. In line, however,
with the present demonstration of moderate LDT projections (and some PPT projections) to the mPFC, previous
reports using various tracers, have similarly identified a
relatively prominent LDT input to the mPFC (Satoh and
Fibiger 1986; Cornwall et al. 1990; Herrero et al. 1991b).
As shown here, they mainly target the ventral mPFC or IL.
These additional afferents undoubtedly supplement those
from AIp and the midline thalamus to IL in relaying limbic
afferent information to IL in visceromotor control.
General summary: an integrative role for the mPFC
in goal directed behavior
Each of the subdivisions of the mPFC receives a fairly
unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor (non-limbic) cortical and thalamic input to dorsal
Brain Struct Funct (2007) 212:149–179
mPFC, to limbic cortical and thalamic (midline thalamus)
input to the ventral mPFC. Each division of mPFC strongly
communicates with immediately adjacent regions, and with
the possible exception of IL, each division interconnects
with all others. The hippocampus (CA1/subiculum) projects heavily to IL and PL, and considerably less so to
dorsal regions of the mPFC. Sites projecting commonly to
the four divisions of mPFC include INC, CLA, BLA, and
TR of the amygdala, parts of the midline thalamus, SUM,
VTA, PAG, DR, MR, and LC of the brainstem.
The AGm (and dorsal AC) receives a vast array of
information both directly and indirectly from all sensory
modalities and presumably utilizes this information in situations demanding immediate attention for appropriate
actions. As discussed, Reep et al. (1990) view AGm as a
multisensory integration region. Stimulation of AGm (and
dorsal AC) produces movements (and generally coordinated movements) of the head, eyes and vibrissa, having
the characteristics of orienting responses. Accordingly,
unilateral AGm lesions disrupt orienting movements and
produce contralateral neglect to visual, auditory and
somatosensory stimuli (Corwin et al. 1986). AGm it is
thought to be homologous to the premotor, supplementary
motor and frontal eye fields of primates (Vertes 2006).
As described, there is a dramatic shift in sources of
afferent information from the AGm/dorsal AC to PL (and
ventral AC), from multisensory afferents dorsally, to a
combination of sensory and limbic input (subcortical/cortical) ventrally. PL is strategically positioned to integrate
information across modalities and compare present and
past events for appropriate actions. In this regard, cells of
PL (and ventral AC) respond selectively during the delay
period of delay response tasks, and PL lesions produce
marked deficits in delayed responses tasks involving short
and long delay—as do lesions of major PL targets (or the
PL circuit) (Vertes 2006). PL (and ventral AC) are thought
to be homologous to the lateral/dorsolateral PFC of primates (Vertes 2006).
Unlike AGm/AC (and PL), afferents to IL almost entirely originate from limbic subcortical and cortical sites.
Visceral afferent information primarily reaches IL via AIp,
BLA and the midline thalamus, and together undoubtedly
represent important sources of limbic input to IL in visceromotor control. As discussed, IL profoundly influences
visceral/autonomic activity (see Introduction). IL is
thought to be homologous to the orbitomedial PFC of
primates (Vertes 2006).
The mPFC of rats, like the prefrontal cortex of primates,
would appear to be directly involved in higher order cognitive functioning, and through interconnections among the
four divisions, would be capable of exerting control over
all aspects, including affective components, of goal directed behavior.
175
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