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ORIGINAL ARTICLE

Anatomical analysis of afferent projections to the medialprefrontal 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 cingu-

late (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 re-

ceive afferent projections from widespread areas of the

cortex (and associated thalamic nuclei) representing all

sensory modalities. This information is presumably inte-

grated 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

reaches the mPFC via the midline thalamus and basal nu-

clei 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 rep-

resent a visceromotor center homologous to the orbitome-

dial 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

W. B. Hoover � R. P. Vertes (&)

Center for Complex Systems and Brain Sciences,

Florida Atlantic University,

Boca Raton, FL 33431, USA

e-mail: [email protected]

123

Brain Struct Funct (2007) 212:149–179

DOI 10.1007/s00429-007-0150-4

CA1,3 Field CA1 and CA3 of Ammon’s horn

CB Cinguum bundle

CC Corpus callosum

CEA Central nucleus of amygdala

CL Central lateral nucleus of the thalamus

CLA Claustrum

CLi Central linear nucleus

CM Central medial nucleus of thalamus

COA Cortical nucleus of amygdala

CP Caudate-putamen

CUN Cuneiform nucleus

DBh Nucleus of diagonal band, horizontal limb

DG Dentate gyrus of hippocampus

DI Dysgranular insular cortex

DR Dorsal raphe nucleus

EC,l,m Entorhinal cortex, lateral, medial divisions

ECT Ectorhinal cortex

EN Endopiriform nucleus

FP,l,m Frontal polar cortex, lateral, medial divisions

FR Fasciculus retroflexus

FS Fundus of the striatum

GI Granular insular cortex

GP Globus pallidus

HF Hippocampal formation

IAM Interanteromedial nucleus of thalamus

IC Inferior colliculus

IF Interfascicular nucleus

IL Infralimbic cortex

IMD Intermediodorsal necleus of thalamus

INC Insular cortex

IP Interpeduncular nucleus

LA Lateral nucleus of amygdala

LC Locus coeruleus

LD Lateral dorsal nucleus of thalamus

LDT Laterodorsal tegmental nucleus

LG,d Lateral geniculate nucleus, dorsal division

LH Lateral habenula

LHy Lateral hypothalamus

LM Lateral mammillary nucleus

LO Lateral orbital cortex

LP Lateral posterior nucleus of thalamus

LPO Lateral preoptic area

LS Lateral septum

LV Lateral ventricle

MA Magnocellular preoptic nucleus

MB Mammillary bodies

MD Mediodorsal nucleus of thalamus

MEA Medial nucleus of the amygdala

MFB Medial forebrain bundle

MG,v Medial geniculate nucleus, ventral division

MH Medial habenula

MO Medial orbital cortex

mPFC Medial prefrontal cortex

MPO Medial preoptic area

MR Median raphe nucleus

MRF Mesencephalic reticular formation

MS Medial septum

MT Mammillothalamic tract

NI Nucleus incertus

NLL Nucleus of lateral lemniscus

NP Nucleus of pons

OC,1,2 Occipital cortex, primary and secondary

divisions

OT Olfactory tubercle

PA Posterior nucleus of amygdala

PAG Periaqueductal gray

PAp Posterior parietal cortex

PARA Parasubiculum of HF

PB, l, m Parabrachial nucleus, lateral, medial divisions

PC Paracentral nucleus of thalamus

PF Parafascicular nucleus

PH Posterior nucleus of hypothalamus

PIR Piriform cortex

PL Prelimbic cortex

PN5 Principal sensory nucleus of trigeminal nerve

PO Posterior nucleus of thalamus

POST Postsubiculum of HF

PPT Pedunculopontine tegmental nucleus

PRC Perirhinal cortex

PRE Presubiculum of HF

PT Paratenial nucleus of thalamus

PV Paraventricular nucleus of thalamus

RAM Radial arm maze

RE Nucleus reuniens of thalamus

RF Rhinal fissue

RH Rhomboid nucleus of thalamus

RLi Rostral linear nucleus

RM Raphe magnus

RN Red nucleus

RPC Nucleus pontis caudalis

RPO Nucleus pontis oralis

RSC Retrosplenial cortex

RR Retrorubral area

RT Reticular nucleus of thalamus

SC Superior colliculus

SF Septofimbrial nucleus

SI Substantia innominata

sm Stria medullaris

SM Submedial nucleus of thalamus

SN,c,r Substantia nigra, pars compacta, pars

reticulata

SSI Primary somatosensory cortex

SSII Secondary somatosensory cortex

SUB,d,v Subiculum, dorsal, ventral parts

150 Brain Struct Funct (2007) 212:149–179

123

SUM Supramammillary nucleus

TE Temporal cortex

TR Amygdalo-piriform transition zone

TT,d,v Taenia tecta, dorsal, ventral parts

V3 Third ventricle

V4 Forth ventricle

VAL Ventral anterior-lateral complex of thalamus

VB Ventrobasal complex of thalamus

VLO Ventrolateral orbital cortex

VM Ventral medial nucleus of thalamus

VO Ventral orbital cortex

VTA Ventral tegmental area

ZI 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 divi-

sions 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), atten-

tional 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, cogni-

tive, and mnemonic processes (Heidbreder and Groe-

newegen 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 vis-

ceromotor 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 pro-

duce pronounced deficits in delayed response tasks (Brito

and Brito 1990; Seamans et al. 1995; Delatour and Gisquet-

Verrier 1996, 1999, 2000; Floresco et al. 1997; Ragozzino

et al. 1998), similar to those seen with lesions of the dor-

solateral PFC of primates (Kolb 1984; Goldman-Rakic

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; Cheat-

wood et al. 2003; Gabbott et al. 2003, 2005), few reports

have examined afferent projections to the mPFC, specifi-

cally 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, Wil-

mington, 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 pentobarbi-

tal. 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 stimu-

lator (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 4�C. Following this, 50 lm

coronal sections were taken on a freezing microtome and

Brain Struct Funct (2007) 212:149–179 151

123

collected in 0.1 M PB and stored at 4�C. 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 Tris-

saline 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 ref-

erence. 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 ta-

ken with a Nikon DXM1200 camera mounted on a Nikon

Eclipse E600 microscope. The photomontages were con-

structed 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 repre-

sentative 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-illus-

trated cases.

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 thin-

ned 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) somato-

sensory 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 baso-

lateral 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 la-

beled (Fig. 1k, l). A few labeled cells were present within

the medial nucleus of amygdala (MEA) and the lateral


123

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

PL

MO

LO

AC

VLOAId

AON

SSI

AIv

SSI

PIR

ACC

AGl

NE

CP

PIR

OT

AId

CLA

SSI

DBh

D

FPm

FPl

FPm

AId

FS

AGl

AId

AC

PL

MO

AGm

AC

PL

ILCLA

VO

AC

AGl

CLA

EN

MS

LS

AC

AGm

CP

ACC

AC

PL

IL CLA

ACC

AGm

AC

PL

IL AId

CP

AGm

OT

SSII

AIp

A

B

C

E

F

G

H

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


123

(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 dorsolat-

erally in RE, and third population dorsally in RH, essen-

tially 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) nu-

clei (Fig. 1m–p). Additional lightly labeled sites at these

levels were the lateral posterior nucleus (LP) of thalamus

and the zona incerta (ZI).

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 ven-

trolaterally 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-

SSI

AC

AGm

SSII

AIp

CP

GPCLA

EN

BST

LHySI

MA

AGm

SSI

AIp

CP

SICEA

RE

PTAM

RT

AH

GP

CS

R

SSII

AIp

CP

SIBLA

RE

PT

AM

LHy

AC

AGm

MS

LSCP

CLA

EN

DBh

GI

GI

PAp

SI

PIR

VALAV

CEA

SSI

AIp

CP

VAL

VMRE

RH

IAM

CEA

BLA

BMA

LHy

RSC

RSC

SSII

PERIRE

RH VM

MD

CP

LHyMEA

BLALA

LD

CL

AGl

VAL

RSCSSI

PERI

MDIMD

CEM

ZILA

BMA

BLA

LHy

RECP

PV

VB

PIR

CEMPO

PH

RSC

SSI

ZI

IMD

PA BLA

PERI

EC

ECT

PFLP

I

J

K

L

M

N

O

P

Fig. 1 continued


123

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 pos-

terior 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 la-

beled 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

EC

PRC

ECT

OC1RSC

PAG

PH

SUMMB

VTA

MRF

POLP

ZI

AUD

PAp

TR

ECT

PRC

EC SUM

CA1

VTA

CA1

SNc

MRF

COA

OC2

TE

MRF

VTAIF EC

OC1

PRC

SC

1AC

SUBv

RSC

AUD

TE

RSC

EC

CLi

IP

PRC

OC2

1A

C

SUBd

PAG

MRF

SNc

OC1

OC1RSCd

TSOP

vB

US

ECm

ECTMRF

RR

CLi

IP

NP

SC

ARAP

DR

ECl

MR

TCE

IC ERP

OC

RPO

RSC

mCE

MRPPT

DR

OC

RPO

LCNI

RPC

5NP

RM

U

V

W

X

RSC

APN

Q

R

S

T

Fig. 1 continued


123

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), la-

beled cells were pronounced within the caudal AC,

dorsomedially, and CLA, ventrolaterally. Light to moder-

ate 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 la-

beled 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,

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 pro-

nounced 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

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


123

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-re-

acted 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 subcor-

tically (Fig. 3u–v), but was nonetheless visible in DR and

LC and to a much lesser degree in the MR, the laterodorsal

PL

MO

VOLO

FPm

FPl

AON

AGm

AIdVLO

MO

PL

AC

VO

AC

PL

IL

AGm

AGl

AId

CLA

OV

IL

AGm

AGm

AC

ILCP

ACCCLA

NEAId

AGl

AGm

AId

ACC

CP

CLA

TTd

SSI

OT

AGlAC

MS

LS

DBh

CP

ENAIp

VP

AC

MA LPO

SI

CP

GP

PIR

BST

AC

AId

SSI

CLAPIR

SF

A

B

C

D

E

F

G

H



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


123

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 predomi-

nantly 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

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). Fig-

ure 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), label-

ing was restricted to dorsomedial and ventrolateral aspects of

AC

RE

RSC

CEA

PTAM

AIp

AV

AH

GI

RSC

SSp

AIp

CP

CEA

RE

PT

AM IAM

LHy

RT

VAL

CLA

AGl

PIR

RSC

SSII CP

VMRE

MD

ALB

LHy

RH

AD

MD

RERHCM

BLA

AL

BMA

CL

PCIMDVB

PIR

PRC

SSIRSC

SSII

AUD

AGl

RSC

ECT

PRC

MD

ZI

LA

BMA

RE

CL

LHy

LD

CM

M

N

O

P

AUD

PV

PHLHy

RSC

ZI

IMD PF

CL

COA

LP

VB

EC

PRC

RSC

PAp

LP

AGm

SSI

PT

SSII

RE

PAG

SUM

VTA

LMEC

ECT

PV

SI

CP

LHyAIp

CLA

RT

CA1

ZI

1AC

PAp

MRF

I

J

K

L

AUD

Fig. 3 continued


123

cortex, CLA, parts of the lateral BF and the midline thala-

mus. 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 ros-

trally, however, labeled cells remained present on the lat-

eral convexity of cortex, in AIp and CLA, rostrally, and

ECT, PRC and anterior EC, caudally (Fig. 5m–p). Sub-

cortically, 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

OC2

APN

IP

RSCOC1

SC

OC1RSC

EC

1A

C

SUBd

SUBv

SUBd

RR

MRF

SC

CLi

IP

PAG

AUD

TE

PAp

vB

US

ECT

GD

TE

ECl

TE

TSOP

RSC

PRC

EC

ECTVTA

SNc

1A

C

PRC

1A

CVTASNc

PAG

RSC

SC

MRF

RN

MRF

IP

MRF

RR

mCE

DR

MR

OC1

NP

RPO

IC

ECl

RSC

OC

MR

PBl

DR

TCE

AQCUN

RPO

OC

mCE

MR

IC

TCE

mCE

LDT

DR

RPC

NI

LC

RPC

5N

P

RM

Q

R

S

T

U

V

W

X

Fig. 3 continued


123

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 label-

ing 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 prom-

inent 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 essen-

tially confined cortically to the ventral subiculum (Fig. 5u)

which was densely labeled, and ECl which was moderately

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, sig-

nificant 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-

Fig. 4 Brightfield


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


123

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), la-

beled 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 neu-

rons were also seen in the EN (Fig. 8g, h).

Mid-levels of the forebrain (Fig. 8i–l) were character-

ized 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

VOLO

FPl

FPmPL

AGm

AIdMO

PL

AC

VLO

AON

AGl

ALC SSI

AGm

EN

CLA

FPm

FPl

AGm

AId

PL

IL

AC

AGm

AC

LS

CP

AC

IL

AGl

GI

AId

ACC

CP

CLA

AGm

AC

IL

CPCLA

AC

PL

ILAId

CLAAONMO

EN

TTv

AGl

ACC

ENAIdAIv

SSI

OTPIR

AId

AIv

SSI

ACC

A

B

C

D

E

F

G

H

SSI



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


123

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 la-

beled cells in the anterior hypothalamus (AH) and LHy,

there was notable absence at labeling within the hypo-

thalamus 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 hypo-

thalamus, densest within the SUM (Figs. 8o, p, 9c). In

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 hippo-

campus (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

AGl

AC

CLA

MS

LS

DBh

CP

ENAIp

OT

SI

SSII

CP

GPCLA

AGm

AC

AIp LPO

SF

MPOMA

SSI

J

K

L

M

N

O

P

VP

PIR

SSII

SSI

AC

AGl

AIp

CP

SI

RE

PVPT AM

RT

LHy

GI

ENCEA

AAPIR

GP

AH

CLA

BLA

PT

AM

AIp

RSC

RE

AV

RT

PV

LHy

CP

GP

SSII

RSCSSI

AIp

CP

RE RH

MD

CEA

BLA

CLA

LHy

VALIAM

PV

PIR

RSC

SSII

AIp RE

RH

MD

CM

LHyBLA

LA

LD

PVVAL

SM

RSCSSI

PRCEC

MD

CM

ZI

LA

BMABLA

LHy

PV

RE

VB

AUD

RSC

MD

CMECT

PRC

PA

PH

BMA

PV

IMD

LP

ZI

CA1

PO

CL

COA BLA

I

TE

PAp

AUD

Fig. 5 continued


123

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, label-

ing 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/me-

dulla (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. Specifi-

cally, 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.

RSC

CA1ECTVTA

PAG

ZI

SUMLM MB

COABLA

TR

EC

MRF

LP

PAp

AUD

SUM

CA1

1AC

ECl

PAG

PH

VTA

PRC

MRF

LP

TR

AUD

OC2

TE

RSCOC1

PRC

1A

C

SUBv

VTA

SNcRN

MRF

SC

ECl

S

T

U

V

W

XOC2RSC

PRC

EClVTA

1A

C

SUBd

SUBvIP

MRF

RR

SC

GD

Q

R

TE

PAG vB

US

ECT

EClCLi

SC

RR

MRF

IP

NP

RSCOC1

mCE

TE

TSOP

DR

SC

MRRPO

PPT

OC1

ERP

RSC

ECT

DR

MR

IC

PAG

RPO

NLL

OC

mCE

LC

rNS

RPC

V4

RM

Fig. 5 continued


123

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-

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

Fig. 6 Brightfield



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


123

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 origi-

nate from limbic cortices and from the midline thalamus.

All regions of the mPFC receive complementary (over-

lapping) projections from the BF, amygdala, hypothala-

mus 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 hypo-

thalamic 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 coex-

tensive 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 cor-

tico-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

Fig. 7 Brightfield



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


123

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 con-

siderably 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-pri-

mates has been described as MD projection cortex (Leon-

ard 1969; Uylings and van Eden 1990). In accord with

several previous reports (Krettek and Price 1977; Groe-

newegen 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

PL

MO

LO

FPm

FPl

AGl

CLA

FPm

CLATTd

OT

AC

SI

SSI

AC

LPOMA DBh

AIdMO

AC

AGl

AGm

PL

ILAId

CLA

AId

AC

IL

MPO

EN

CLA

AGm

AIp

MS

DBh

CPLS

AGm

AC

CP

ACCLS

IL

PL

CP CLA

ACC

EN

AGm

AON

CLAACC

PIR

AId

AGl

GP

SFCP

AIp

SSII

A

B

C

D

E

F

G

H

SSI

SSI

SSIIGI

AGl

VP



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


123

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 thala-

mus. Consistent with this, Hicks and Huerta (1991) de-

scribed 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 pro-

nounced 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).

GI

AC

FI

MD

RSCSSI

AIp

ALB

RERH CLA

PV

IAM

VM

LHy

VAL

PIR

CEA

CP

TE

SSII

PV

CM

MD

RERH

CM

IMD

BLALA

PIR

VB

RSC

L

RSC

MD

CMECT

PHLHy

BMABLA

PA

PV

IMD

ZI

LP

AUD

PAp

PAp

TE

AUD

SUMm

SUMm

RSC

CA1

1

CA1

SUBvSUM

VTA

SNc

BLAAEM

SC3A

C

TRCOA

EC

RSCOC2

PAp

AUD

GI

AIp

CP

RE

AMPT

GP

SI

CLA

BLA

LHy

AGm

SSI

AIpLHy

PV

IAM

RE

AM

RSC

GI

PRC

MD

RH

RE

PRC

PRC

ECT

SUM

PH

PAG

PV

PIR

CEAAH

AGl

AV

VAL

RH

CEA

PIR

VBSSII

LHy

LD

MB

BLACOA

ZI

TR

EC

LP

MRF

I

J

K

M

N

O

P

SSII

AGl

Fig. 8 continued


123

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 (Mark-

owitsch 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

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 De-

naro 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

SNc

MRF

VTAIF

RSC

EC

ECT

SUBv

SC

RLi

SUBd

Q

R

OC1

AUD

AUD

RSC

1AC

RN

MRFMG

IP

rNS

SC

OC2

RSC

OC1

TE

CLi

1A

C

SUBd

SUBv

VTA

ECl

MRF

SC

SNc

ECT

RR

PAG

SC

DR

RSC

ERP

RAP

mCE

ECT

MR

NLL

NP

PPT

IC

mCE

ECl

ECT

DR

MR

PAG

IC

RPO

CUN

OC1RSC

MR

PB

IC

RPO

DR

LDT

OC2

mCE

TCE

S

T

U

V

W

X

NILDT

RPC

PRC

EC

1A

C

VTA

RSC

TSOP

mC

E

ECT

vB

US

SUBv

NP

IP

OC1

TE

Fig. 8 continued


123

Fig. 10 Brightfield


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

Fig. 9 Brightfield



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


123

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;

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 pro-

jections (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

Non-LimbicCortex

BasalForbrain

Thalamus

Hypothalamus

LimbicCortex

Midbrain Pons/medulla

AGm

FPmAGmSSISSIIOC2RSC

AGlGIAUDPApOC1TE

CLA

DBhSIMA

GPVP

CLMDCMPVRHREVMPT

AMIAMIMDPCVAL

LP

LHyPH

ZISUM

AmygdalaBLA

BMAMEAPATR

VTA

SNcPAGSUMCLi

MRFIP

DRPPTLC

MRNI

RPORPC

MOVOVLOACPLAIdAIpPRC

ILECTEC

CA1LO

Non-LimbicCortex

LimbicCortex

BasalForbrain

Thalamus

Hypothalamus Midbrain Pons/medulla

AC

ACPL

ILMOVOPRCECCA1

AIpECT

CLA

SITTd

BSTDBhLPOMA

AMCLRERHIAMMDPC

CLCMIMDPVPCVM

PT

AmygdalaLHyPAGPH

SUMLM

BLABMA

AGmPApRSCOC2FPmAUDAGlGITESSII

VTA

SNcIPCLi

DR

LCNILDT

MRPB

A

B

heavy labeling

light labeling

moderate labeling

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


123

(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 affer-

ents 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.

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

Non-LimbicCortex

BasalForbrain

Thalamus

Hypothalamus

LimbicCortex

Midbrain Pons/medullaAmygdala

A

IL

FPmRSC

DBhCLA

TTdEN

MSLSMPOSI

RERHPTPVMD

IAM

IMDCM

SUM

LHyAHPAG

BLABMATR

COALAPA

ILCA1SUB

PLAIpPRCEC

ACECT

VTACLi

PAGSNc

DRLDT

MRLC

NIRPO

Non-LimbicCortex

LimbicCortex

BasalForbrain

Thalamus

Hypothalamus Midbrain Pons/medullaAmygdala

B

PL

FPm

AGm

RSC

CLA

TTdDBhLPO

ENVP

PTPVMDRERH

IMDIAM

CL

SUM

LMLHyPH

BLABMA

TR

PACOA

MOVOACPLILAIdAIvAIpCA1SUBPRC

EC

ECT

VTA

PAGIPSNc

DR

LCMR

heavy labeling

light labeling

moderate labeling

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. 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


123

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 tar-

gets AC. Based on extensive RSC connections with AC,

and additionally with parts of the limbic thalamus, subic-

ulum/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/sec-

ondary 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 ne-

glect (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 pre-

viously.

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 projec-

tions from the hippocampus (CA1/subiculum) to the ven-

tral 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

mid-lateral regions of the thalamus. This involves projec-

tions 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 origi-

nating from the ventromedial AM. As has been demon-

strated (Sripanidkulchai and Wyss 1986; Shibata and Kato

1993; van Groen et al. 1999), there are marked differ-

ences in projections from the anterior thalamus to the

anterior and posterior AC (or RSC), such that AM dis-

tributes 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 re-

cently been demonstrated using anterograde tracers

(Vertes et al. 2006).

Other inputs to AC

Similar to AGm, AC receives input from several (non-

thalamic) subcortical sites including the CLA, TTd, MA,

SI, BST of the BF, the BLA/BMA of amygdala, the pos-

terior 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.


123

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 re-

gions (RSC and PAp) of cortex, to the ventral as com-

pared 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 dem-

onstrations of significant orbital and limbic cortical affer-

ents 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) pri-

marily 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 dem-

onstrated massive hippocampal projections (CA1/subicu-

lum) 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 pro-

jections 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 thal-

amus is an important relay in the transfer of information

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/su-

biculum) (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 dis-

tribute densely to PL. Previous reports using anterograde or

retrograde tracers have described similar findings (Her-

kenham 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 distrib-

ute 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) par-

ticipate 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 func-

tions, 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 dis-

tributes to a relatively small groups of structures that

subserve cognition and have been designated the ‘PL cir-

cuit’ (Alexander et al. 1990; Groenewegen et al. 1990).

They mainly include the insular cortex (AId), the hippo-

campus (via RE), CLA, ACC, BLA, MD, RE, and VTA.

Lesions of each of these structures, like those of PL, pro-

duce deficits in delayed response tasks and memory (Har-

rison 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 PL-

associated 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


123

PL and dopamine (D1) receptors at PL disrupted perfor-

mance 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 hip-

pocampus (CA1/subiculum) distributes massively to IL. If,

as indicated, IL represents a visceromotor center, hippo-

campal 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 frustra-

tions (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-

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 baso-

lateral (BLA) and TR of amygdala, and the SUM of the

hypothalamus. In contrast, the midline thalamus, particu-

larly 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 demon-

stration 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 projec-

tions 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 projec-

tions (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 dorso-

ventrally along the mPFC from predominantly sensorimo-

tor (non-limbic) cortical and thalamic input to dorsal


123

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) pro-

jects 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 sit-

uations 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 coordi-

nated 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/cor-

tical) 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 pri-

mates (Vertes 2006).

Unlike AGm/AC (and PL), afferents to IL almost en-

tirely 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 vis-

ceromotor 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 cog-

nitive functioning, and through interconnections among the

four divisions, would be capable of exerting control over

all aspects, including affective components, of goal direc-

ted behavior.

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