THE JOURNAL OF COMPARATIVE NEUROLOGY 450:345–365 (2002)
Comparison of Hippocampal, Amygdala,
and Perirhinal Projections to the
Nucleus Accumbens: Combined
Anterograde and Retrograde Tracing
Study in the Macaque Brain
DAVID P. FRIEDMAN,1 JOHN P. AGGLETON,2* AND RICHARD C. SAUNDERS3
1
Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
2
School of Psychology, Cardiff University, Cardiff, Wales CF10 3YG, United Kingdom
3
Laboratory of Neuropsychology, NIMH, Bethesda, Maryland 20892
ABSTRACT
A combination of anterograde and retrograde tracing techniques was used to study the
projections to the nucleus accumbens from the amygdala, the hippocampal formation (including
the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help
identify possible subregions within the nucleus accumbens, the distribution of calbindin was
examined in two additional monkeys. Although this revealed evidence of “core”- and “shell”-like
regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the
medial and the lateral portions of nucleus accumbens, whereas projections arising from the
middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude
topography as parts of the basal and accessory basal nuclei terminated in different parts of
nucleus accumbens. The subiculum was the major source of hippocampal projections to the
nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the
prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal
projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in
the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and
ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle.
The entorhinal projections were more evenly distributed between the medial nucleus accumbens
and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory
tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.
J. Comp. Neurol. 450:345–365, 2002. Published 2002 Wiley-Liss, Inc.†
Indexing terms: nucleus accumbens; ventral striatum; entorhinal cortex; perirhinal cortex;
monkey; fornix
The nucleus accumbens is a major component of the
ventral striatum, which also comprises the immediately
adjacent portions of the caudate nucleus and putamen and
the deep layers of the olfactory tubercle. The ventral striatum is richly innervated by projections from limbic regions (Heimer et al., 1982; Groenewegen et al., 1991),
distinguishing it from the dorsal striatum. These inputs
help to establish this region as functionally unique (Mogenson et al., 1980; Heimer et al., 1982; Everitt and Robbins, 1992; Haber and Fudge, 1997). Two of the principal
PUBLISHED 2002 WILEY-LISS, INC. †This article is a US
Government work and, as such, is in the public domain in the
United States of America.
*Correspondence to: John P. Aggleton, School of Psychology Cardiff
University, Park Place, PO Box 901, Cardiff, Wales CF10 3YG, United
Kingdom. E-mail: [email protected]
Received 10 March 2000; Revised 12 February 2002; Accepted 15 May 2002
DOI 10.1002/cne.10336
Published online the week of July 22, 2002 in Wiley InterScience (www.
interscience.wiley.com).
346
D.P. FRIEDMAN ET AL.
sources of limbic inputs to the nucleus accumbens are
from the amygdala and the hippocampal formation. These
projections have been described in detail for the rat brain
(Krettek and Price, 1977; McDonald, 1991; Brog et al.,
1993; Wright et al., 1996), but considerably less is known
about them for the monkey brain.
Nauta (1961) was the first to describe a direct projection
from the amygdala to the ventral striatum in the monkey.
Russchen et al. (1985), using Macaca fascicularis, subsequently provided evidence of a coarse topography in the
projections from the amygdala to the ventral striatum.
Clear differences were found in the density of terminations in the medial and lateral portions of nucleus accumbens from projections arising in different parts of the
basal and accessory basal nuclei (Russchen et al., 1985).
Although these studies confirmed that there is a complex
pattern of amygdala–ventral striatal projections, it was
not known at the time how these amygdala termination
patterns might relate to subregions within the ventral
striatum, such as the “core” and “shell” of nucleus accumbens (Zaborszky et al., 1985; Martin et al., 1991; Meredith
et al., 1995; Brauer et al., 2000). Furthermore, our knowledge of the source of these inputs had remained imprecise,
being based largely on the placement of anterograde tracers in the amygdala (Russchen et al., 1985). More precise
information was provided in a recent study using both
anterograde and retrograde tracers in Macaca nemestrina
(Fudge et al., 2002). This study confirmed that the basal
and accessory basal nuclei are the principal sources of the
amygdala input to ventromedial striatum.
We have less knowledge concerning the details of the
projections from the hippocampus and parahippocampal
cortices to the ventral striatum in monkeys. It is known
that the hippocampus, and in particular the subicular
complex, projects to the nucleus accumbens and the olfactory tubercle (Siegel et al., 1975; Rosene and Van Hoesen,
1977; Aggleton et al., 1987), and that these projections
pass through the precommissural component of the fornix
(Siegel et al., 1975; Poletti and Cresswell, 1977). It is not
clear, however, whether all portions of the monkey nu-
cleus accumbens receive a hippocampal input, or how
these projections relate to the shell and core distinction. It
also remains to be determined which components of the
subicular complex provide the various striatal afferents
and whether, as in the rat, there is a contribution from
field CA1 (Van Groen and Wyss, 1990; Brog et al., 1993).
In the rat, both the entorhinal and the perirhinal cortices
project to the ventral striatum (Brog et al., 1993), and,
although it is likely that these same regions have similar
projections in monkeys, such inputs remain to be described.
The present study used both anterograde and retrograde tract tracing techniques to examine these medial
temporal–ventral striatum connections in two species of
macaque monkey. To determine whether hippocampal inputs rely on both fornical and nonfornical pathways
(Meibach and Siegel, 1977; Rosene and Van Hoesen, 1977;
Aggleton et al., 1986), the fornix was transected in some of
the monkeys before they received injections of tritiated
amino acids into limbic sites. A final group of monkeys
was prepared using immunohistochemical techniques to
reveal relative densities of calbindin within the ventral
striatum (Zahm and Heimer, 1988; Martin et al., 1991;
Meredith et al., 1996). This made it possible to relate the
results of the study to the regions of calbindin-positive
(core-like) and calbindin-negative (shell-like) staining in
the nucleus accumbens (Meredith et al., 1995)
MATERIALS AND METHODS
All experimental procedures were carried out under
NIMH- or Wake Forest University-approved animal study
protocols, with strict adherence to the NIH Guide for Care
and Use of Laboratory Animals. Because our initial anterograde and retrograde studies found no evidence of
limbic projections that cross to the ventral striatum in the
contralateral hemisphere, injections of tracers were
placed in both hemispheres in certain animals.
Abbreviations
AB
ABmc
ABpc
AC
Bi
Bmc
BNST
Bpc
CA1, CA2,
CA3, CA4
Cd
Ce
Cel
Cem
Ch2, Ch4
CTA
DC
DG
GP
IC
L
M
NASL
NASM
accessory basal nucleus
accessory basal nucleus, magnocellular division
accessory basal nucleus, parvicellular division
anterior commissure
basal nucleus, intermediate division
basal nucleus, magnocellular division
bed nucleus of the stria terminalis
basal nucleus, parvicellular division
hippocampus ammonic subfields
caudate nucleus
central nucleus of amygdala
central nucleus, lateral division
central nucleus, medial division
basal forebrain cholinergic cell groups
cortical amygdaloid transition area
dorsal cone, nucleus accumbens
dentate gyrus
globus pallidus
islands of Calleja
lateral nucleus of amygdala
medial nucleus of amygdala
nucleus accumbens, lateral
nucleus accumbens, medial
OTr
P
PAC
PaS
Pl
PoS
PrS
RS
S
SI
TOL
TOL2
TOL3
V
14
25
28
28I
28L
28M
28S
35
36
olfactory tract
putamen
periamygdaloid cortex
parasubiculum
paralaminar nucleus
prosubiculum
presubiculum
rhinal sulcus
subiculum
substantia innominata
olfactory tubercle
olfactory tubercle, region 2
olfactory tubercle, region 3
ventricle
Brodman’s area 14, medial frontal cortex
Brodman’s area 25, medial frontal cortex
Brodman’s area 28, entorhinal cortex
intermediate entorhinal cortex
lateral entorhinal cortex
medial entorhinal cortex
sulcal entorhinal cortex
Brodman’s area 35, perirhinal cortex
Brodman’s area 36, perirhinal cortex
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
Anterograde transport studies
Eighteen cynomolgus monkeys (M. fascicularis) weighing from 2.7 to 5.7 kg and six rhesus monkeys (M. mulatta)
weighing from 1.7 and 7.0 kg were used for the tracing
studies. Prior to the injection, all animals were sedated
with ketamine hydrochloride (10 mg/kg), deeply anesthetized with Nembutal (35 mg/kg), and placed in a stereotaxic apparatus. Each animal received an injection of an
equal-parts mixture of tritiated proline (New England
Nuclear, Boston, MA; L-[2,3,4,5H], specific activity 139
Ci/mmole) and leucine (New England Nuclear; L-[3,4,5H],
specific activity 111 Ci/mmole). Most injections were made
through a 1 ␮l Hamilton syringe at a final concentration of
50 ␮Ci/␮l, although some of the rhinal injections (Erh1,
Erh2, Erh3, Prh1) were at a concentration of 100 ␮Ci/␮l.
Furthermore, in this set of animals, the injectate consisted
of an equal parts mixture of leucine, lysine, proline, and
an amino acid combination derived from an algal protein
hydrolysate (Saunders and Rosene, 1988).
After an interval of 6 or 7 days, the monkeys were
sacrificed with a lethal dose of Nembutal (100 mg/kg i.v.)
and perfused through the left ventricle with normal saline, followed by neutral buffered formalin. The brains
were cryoprotected with 30% sucrose solution prior to
being cut in 33 ␮m coronal sections on a freezing microtome. Every sixth section was mounted on a glass slide
from either phosphate buffer or Perfix and then coated
with Kodak NTB2 emulsion. The sections were exposed at
40°C for 6 –30 weeks, developed in Kodak Dl9, fixed, and
counterstained with thionine. In four cases (ERh1, ERh2,
ERh3, PRh1), the fixed brain was embedded in paraffin
and then cut into 10 ␮m sections using a rotary microtome. Every twentieth section was mounted on glass
slides and coated with emulsion.
Amygdala injections
Nine cynomolgus monkeys received single injections of
between 0.1 and 0.5 ␮l of the amino acid mixture in the
amygdala complex. Injection coordinates were derived
from skull landmarks revealed on X-rays (Aggleton, 1985).
Six monkeys received unilateral injections (ACy6, ACy10,
ACy13, ACy16, ACy17, ACy18), whereas three received
bilateral injections (ACy20, ACy21, ACy22), making a total of 12 injection sites. The sites in the bilateral cases are
designated R or L accordingly. An additional monkey
(ACy2) received multiple, unilateral injections within the
amygdala totaling 1 ␮l.
Hippocampal injections
Seven cynomolgus (all “ACy”) and one rhesus monkey
(ARhF24) received amino acid injections in the hippocampal formation. Single injections of 0.10 – 0.20 ␮l were made
in four cases (ACy12, ACy14, ACyF15, ACyF19), the remainder receiving multiple injections totaling 0.24 – 0.44
␮l. One case (ACyF27L) received bilateral hippocampal
injections. The coordinates for the hippocampal injection
were determined with the aid of electrophysiological recordings made prior to the injection. A tungsten microelectrode was lowered into the hippocampal region, and the
various cell layers were identified by their resting activity.
In five of the animals given hippocampal formation isotope
injections, the fornix had been completely transected bilaterally between 2 and 10 months earlier (all such cases
are designated ACyF or ARhF depending on the species).
347
The surgical procedure and the completeness of the lesions have been fully documented elsewhere (Bachevalier
et al., 1985). It should be noted that fornix transection
does not result in cell loss in the hippocampal formation
(Daitz and Powell, 1954), and the cells remain capable of
transporting amino acids (Aggleton et al., 1986). For this
reason it is valid to compare the hippocampal efferents in
cases with and without an intact fornix.
Perirhinal and entorhinal cortex injections
Three rhesus monkeys received amino acid injections in
the entorhinal cortex. Two cases (ERh1, ERh2) received
single, small injections of 10 ␮Ci and 20 ␮Ci in areas 28M
and 28l, respectively. In the third case (ERh3), six injections, each of 20 ␮Ci, were placed throughout the entorhinal cortex. Two other monkeys received single injections
in the perirhinal cortex. These were at the midrostrocaudal level of 35 and 36 (rhesus monkey, case PRh1) and at
the caudal limit of 35 and 36 (cynomolgus monkey, case
ACy9). In two further cases, the fornix was cut bilaterally
prior to injections into caudal area 35 (rhesus monkeys,
case ARhF23) or the subiculum and midarea 36 (cynomolgus monkey, case ACyF27R).
Retrograde transport studies
The surgical procedures were essentially the same as
those described for the anterograde tracers, except that
the injections were made under visual guidance. For this,
a small cut was made through the corpus callosum over
the lateral ventricle, allowing visualization of the ventricular walls close to nucleus accumbens. Four rhesus monkeys (NaRh1, NaRh2, NaRh3, NaRh4) received injections
of either diamidino yellow (Keizer et al., 1983) or fast blue
(Kuypers et al., 1980) made through a 5 ␮l Hamilton
syringe fitted with a 28 gauge needle. The fast blue (FB;
Sigma) and diamidino yellow were both injected as 3%
suspensions in normal saline. In two animals (NaRh1,
NaRh2), these injections were directed at nucleus accumbens, so that one tracer (e.g., diamidino yellow) was targeted at the medial division, whereas the other tracer
(e.g., fast blue) was targeted at the lateral division in the
same hemisphere. In the other two monkeys (NaRh3,
NaRh4), single injections of fast blue and diamidino yellow were placed in the opposite hemispheres. One tracer
was targeted at the lateral nucleus accumbens, the other
at the medial nucleus accumbens.
After a postoperative recovery period of between 7 and 9
days, the animals were deeply anesthetized with Nembutal (100 mg/kg i.v.) and perfused transcardially with saline, followed by approximately 2 liters of 4% paraformaldehyde in 0.1 M cacodylate buffer (pH 7.4). The brains
were then removed and placed in a series of cryoprotectant solutions from 10% to 20% glycerol in cacodylate
buffer (Rosene et al., 1986) and then rapidly frozen by
immersion in –75°C isopentane. The brains were blocked
in the coronal plane, and a 40 ␮m series was cut on a
freezing microtome. Three series were saved at an interval
of 200 ␮m and were mounted (Fluromount; Gurr), dried,
and coverslipped. All sections were stored in the dark at
4°C.
Calbindin immunohistochemistry
Two adult rhesus monkeys (Rh1 and Rh3) were prepared for immunohistochemistry so that the distribution
of calbindin might be related to the results of the tracing
348
D.P. FRIEDMAN ET AL.
Fig. 1. Photomicrographs of two coronal sections through the
midlevel of nucleus accumbens in the Macaca mulatta brain. Left:
Nissl-stained section depicting the NASM, NASL, and TOL. Right:
Distribution of calbindin in ventrial striatum showing the calbindinrich region in the NASL and the calbindin-light region in the NASM.
TOL is also lightly stained for calbindin. The NASM and the NASL are
more easily discernible on the calbindin-stained sections. Cytoarchtectonic features distinguishing between medial and lateral NAS and
between NASL and the rest of the ventral striatum are not readily
delineated. For this reason, the boundary lines are broken. Scale
bars ⫽ 1 mm.
studies. The monkeys were initially injected with ketamine (10 mg/kg i.m.) and given a lethal overdose of sodium pentobarbital (100 mg/kg i.v.). They were then transcardially perfused with Ringer’s solution, followed by 4%
paraformaldehyde in 0.1 M phosphate buffer (pH 7.4).
Brains were removed, blocked, and cryoprotected with a
glycerol/dimethylsulfoxide (DMSO) solution and then frozen in isopentane at –35° to –55°C and stored at – 80°C.
The tissue was cut in the coronal plane on a freezing
microtome into 33 ␮m sections. Sections were first washed
with phosphate-buffered saline (PBS; pH 7.4), followed by
a block to inhibit endogenous peroxidase. For this, sections were pretreated in 0.3% H2O2 and 10% methanol for
10 minutes and then rinsed twice in PBS. They were then
placed in 2% normal horse serum overnight at 4°C in a
monoclonal antibody to calcium binding protein (CaBP;
Sigma Chemical Co., St. Louis, MO) at a dilution of
1:20,000. Sections were then incubated with the secondary
antibody according to the Vector Elite ABC methodology
(Vector Laboratories, Burlingame, CA), and nickel intensification of DAB was used to aid visualization. Sections
were then mounted onto chromalum/gelatin-coated slides,
dried, and coverslipped.
core (Zaborszky et al., 1985; Zahm and Brog, 1992). A
similar division has been described for the primate brain,
including the macaque brain (Friedman et al., 1992;
Meredith et al., 1995). This distinction has largely been
based on the presence of a calbindin-D28k-negative region
in the medial and ventral portions of nucleus accumbens,
which has been considered as homologous to the shell
region observed in the rat ventral striatum. This shell-like
region occupies the medial and ventral portions of striatum, beginning rostrally where the internal capsule begins to separate the caudate nucleus from the putamen
and ending caudally at the rostral pole of the bed nucleus
of the stria terminalis (BNST).
Although a clear division within nucleus accumbens can
be seen in sections from a rhesus monkey stained to reveal
calbindin (Fig. 1), there is no obvious, corresponding cytoarchitectonic border. The use of calbindin immunohistochemistry did, however, direct our attention to a subtle
cytoarchitectonic border that separates a medial (and ventral) division from a lateral (and dorsal) division within
nucleus accumbens. In the cynomolgus macaque, the medial division appeared to correspond closely to the
calbindin-negative, shell-like region, whereas the lateral
division closely corresponds to the calbindin-positive, corelike region. This division is most apparent in the midrostrocaudal region of the structure. The cells in the medial
division are packed less densely than those in the lateral
division (Fig. 1). In addition, the cells of the lateral division appear aligned in a diagonal plane, whereas neurons
in the medial division are not as clearly organized in any
particular orientation. The lateral division appears continuously with the putamen. The medial division also
contains a population of noticeably larger neurons that
are not seen laterally. Within this medial division, there is
Nomenclature and identification of areas
Nucleus accumbens. In the primate, the ventral striatum comprises the nucleus accumbens, the deep layers or
“striatal” part of the olfactory tubercle, and the medial
portion of the ventral putamen and the ventromedial caudate immediately adjacent to the nucleus accumbens (see
Heimer et al., 1982; Haber et al., 1994). In the rat brain, it
is possible to divide the nucleus accumbens into a medial
and ventral division, commonly called the shell, from a
more central and lateral division, commonly called the
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
349
Fig. 2. Location of amygdala injections of anterograde tracer. The
leftmost section, through the midlevel of the amygdala in the macacque brain, depicts the arrangement of the major nuclei and their
nomenclature. The four sections show the center of each amino acid
injection. More details on these injections can be found in Aggleton
and Mishkin (1984). The large entorhinal injection (case ERh3) is
depicted at one level (see also Fig. 6). For abbreviations see list.
often a cell-sparse region immediately lateral to the islands of Calleja. A dorsal “cone” of more densely packed
cells can also be seen at the midlevel of the medial division. When possible, these cytoarchitectonic guides were
used to assist in determining the position of label within
the nucleus accumbens. In the rhesus monkey, nucleus
accumbens is similarly arranged, but the changes between
the medial and the lateral divisions are less apparent and
are seen as a transition rather than a border. The lack of
a reliable border that can be directly related to the core
and shell distinction means that the results are described
in relation to the medial and lateral position with nucleus
accumbens.
Olfactory tubercle. The olfactory tubercle, which is
located on the ventral surface of the brain caudal to the
anterior olfactory nucleus, has been divided into three
regions; TOL1, TOL2, and TOL3 (Crosby and Humphrey,
1941; Turner et al., 1978). Each region has three lamina.
The deeper portions of lamina III have been described as
the striatal portion of the olfactory tubercle (Heimer,
1978). This deep portion consists of a region of mediumsized cells, very similar to those in the nucleus accumbens
(Fig. 1). This region is not readily separable from the
nucleus accumbens in Nissl-stained sections, even though
the cells in the tubercle are somewhat less regularly distributed than those in the nucleus accumbens. As with the
medial division of the nucleus accumbens, the olfactory
tubercle stains lightly for calbindin so that the two structures appear continuous on calbindin-stained sections
(Fig. 1).
Hippocampal formation and perirhinal cortex. The
nomenclature for the hippocampal region is derived from
the classic work of Lorento de No (1934). The term hippocampal formation includes the hippocampus proper
(Ammon’s horn), the dentate gyrus, and the subicular and
entorhinal cortices. Divisions of the entorhinal cortex are
taken from the descriptions of Saunders and Rosene
(1988). The perirhinal cortical designations, areas 35 and
36 (Brodman, 1909), follow those of Amaral et al. (1992)
and match those of Saleem and Tanaka (1996) and Saleem
and Hashikawa (1999).
Amygdala. The cytoarchitectonic divisions of the
amygdala follow those originally proposed by Crosby and
Humphrey (1941) and subsequently adapted for the monkey (Amaral et al., 1992; Saunders and Rosene, 1988).
Preparation of photomicrographs
Photomicrographs were taken using a digital camera
attached to either a Zeiss axiophot microscope or an Olympus SZ60 microscope. Images were transported directly
into Adobe Photoshop and Illustrator. Alterations for
print quality were limited to contrast and brightness,
which were used to clarify the images. At the same time,
care was taken to ensure that key features, such as injection sites, were represented faithfully. Images were
cropped and magnification adjusted to fit within a figure.
Prints were made using a dye sublimation printer.
RESULTS
Anterograde tracers
Projections from the amygdala to the nucleus accumbens and olfactory tubercle. Figures 2 and 3 depict the placement and extent of the injections of tritiated
amino acids into the amygdaloid complex. The injection
sites are considered to correspond to the area in which
silver grains filled the neuropil and perikarya at a density
that was appreciably above background. More details of
these injection sites can be found in Aggleton et al. (1984).
Projections to the nucleus accumbens originated in a variety of amygdala nuclei; terminal label was found in the
nucleus accumbens in all cases except those in which the
injection was centered in the lateral nucleus (ACy16,
ACy22R). The termination of these projections within the
nucleus accumbens is described with regard to its medial
and lateral cytoarchitectonic divisions (see above under
Nomenclature and identification of areas).
350
Fig. 3. Photomicrographs of coronal Nissl-stained sections showing the center of the amino acid injections in cases ACy22L, ACy18,
and ACy21L (top row) and ACy10, ACy20L, and ACy20R (bottom
Fig. 4. Darkfield photomicrograph of a coronal section showing the
nucleus accumbens in both hemispheres in case ACy2. This low-power
photomicrograph shows the exclusively ipsilateral nature of the projection from the amygdala to nucleus accumbens. Case ACy2 received
large injections of amino acids centered in the basal and accessory
basal nuclei of the amygdala. Scale bar ⫽ 1 mm.
Crossed projections. In two cases (ACy2, ACy6) relatively large injections were placed unilaterally in the
amygdala (Fig. 2). These involved almost all of the basolateral nuclei and in case ACy2 extended into the entorhi-
D.P. FRIEDMAN ET AL.
row) with amygdala injections. All examples had 14 weeks of exposure. The dashed lines show the major nuclear boundaries within the
amygdala. For abbreviations see list. Scale bars ⫽ 1 mm.
nal cortex. Although dense label was observed in the ipsilateral ventral striatum, there was no evidence that
these projections crossed to the contralateral ventral striatum (Fig. 4). For this reason, a number of subsequent
cases received bilateral amygdala injections, and it is assumed that no label crossed to the contralateral striatum.
This assumption was supported by the retrograde tracer
studies.
Basal nucleus projections. The most dense label in the
ventral striatum was seen after injections into the basal
nucleus (ACy6, ACy21L, ACy10, ACy21R, and ACy13).
Even though the injections were centered in different regions within this nucleus (Figs. 2, 3, 5), all of them labeled
the medial and ventral portions of the nucleus accumbens
at all rostrocaudal levels. All of these cases also showed
label in the lateral portion of nucleus accumbens, but this
was almost always appreciably lighter (case ACy13 being
the only exception). The nucleus accumbens label seemed
especially dense when the injection involved the intermediate and magnocellular divisions of the basal nucleus
(ACy21R, ACy21L). The adjacent, striatal portion of the
olfactory tubercle was also labeled in all five of these
cases.
Case ACy21L (Fig. 6 upper) is an example of an injection centered in the intermediate division of the basal
nucleus (Fig. 3). Label was most dense at the caudal limits
of nucleus accumbens, where it appeared continuous with
heavy label in the BNST. In addition to the rostrocaudal
gradient, there was also a clear medial ventral– dorsal
Figure 5
352
lateral gradient. Most label was present in the medial
ventral portion. Consistently with this, the label in the
lateral division was largely confined to the more medial
and ventral parts. The only exception to this pattern was
at the most rostral limit of nucleus accumbens, where the
light label was distributed evenly across the medial and
lateral portions of the nucleus. Within the medial division
there was, however, a noticeable absence of label in the
cell-sparse region immediately lateral to the islands of
Calleja. Dense, uniform label was also present throughout
the striatal portions of areas TOL1–3 of the olfactory tubercle. This label, which was continuous with that in
nucleus accumbens, also extended ventrally into lamina
II, and the deeper part of lamina I in TOL3 (see Aggleton
et al., 1987). Finally, light patches of label were found in
the ventral putamen, immediately lateral to the nucleus
accumbens.
Very similar, but lighter, label was found in cases
ACy21R and ACy6 (Fig. 6, middle). In both cases, the
injection involved primarily the intermediate and magnocellular divisions of the basal nucleus, and, in both cases,
label was concentrated in, but not restricted to, the medial
and ventral regions of nucleus accumbens, corresponding
to the medial division. As in case ACy21L, there was an
absence of label immediately lateral to the islands of
Calleja. Again, label was present throughout the striatal
portion of the olfactory tubercle.
Injections placed in the parvicellular division of the
basal nucleus produced a pattern of label similar to that
with injections into the intermediate and magnocellular
divisions (Fig. 7, top). In case ACy10, the injection was
largely restricted to the parvicellular basal nucleus (Fig.
3) but extended ventrally into layer VI of the entorhinal
cortex (which does not appear to contribute to the accumbens projection). In this case (ACy10), the distribution of
label in nucleus accumbens, the olfactory tubercle, and the
adjacent part of the ventral putamen was very similar to
that in ACy21L and ACy6 (Fig. 7, top). The only differences were that, in ACy10, the label in the olfactory tubercle was less dense and was confined to the striatal
portion of TOL2 and TOL3, and the medial to lateral
gradient in nucleus accumbens was less apparent in that
the label involved the medial half of the lateral division as
well as the medial division (Fig. 7, top). As before, the
label at the rostral limit of nucleus accumbens was evenly
distributed across the entire medial and lateral portions of
the nucleus. Within the medial division, the label was
largely absent from the cell-sparse region just lateral to
the islands of Calleja. Case ACy13, which had a more
caudal injection in the parvicellular basal nucleus (Figs. 2,
Fig. 5. (Overleaf). Lightfield (left column) and darkfield (right
column) photomicrographs of coronal sections showing the injection
sites (left) and distribution of transported amino acid (right) in the
nucleus accumbens and olfactory tubercle in selected cases. Top row:
Injection centered in the parvicellular division of the basal nucleus of
the amygdala (ACy13), with label in medial nucleus accumbens; second row: injection centered in subiculum (ACy14), with label in medial nucleus accumbens and lighter label in deep layers of olfactory
tubercle; third row: large injection involving most of entorhinal cortex
(ERh3), resulting in anterograde label in medial nucleus accumbens
(except the dorsal cone) and olfactory tubercle; bottom row: injection
in area 35 and adjacent 36 (PRh1) with anterograde label principally
concentrated in the olfactory tubercle. Scale bars ⫽ 1 mm.
D.P. FRIEDMAN ET AL.
5) that extended into the most rostral hipocampus, revealed a pattern of anterograde label similar to that of
ACy10. The only differences was that, in ACy13, the density of labeling was more evenly distributed across the
medial and lateral divisions of nucleus accumbens (Fig. 5).
Accessory basal nucleus projections. Injections were
placed in the accessory basal nucleus in three cases
(ACy18, -20L, -20R). In all three cases, the injections
appeared confined to the nucleus (Figs. 2, 3). In both
ACy20L and ACy20R, the injection sites were centered in
the magnocellular (dorsal) division of the nucleus (Fig. 3).
Very light, scattered label was observed in the caudal
two-thirds of nucleus accumbens (Fig. 7, middle). In both
cases, the most dense label was located in the cell-sparse
zone immediately lateral to the islands of Calleja. In this
region, the labeling pattern seen after injections into the
magnocellular division of the accessory basal nucleus was
complementary to the labeling pattern seen after injections in the basal nucleus, which showed no label in this
area but dense label immediately lateral to it. There was
no label in the putamen. A distinct but light region of
label, immediately deep to lamina II, was found in both
TOL2 and TOL3. No other label was seen in TOL2, but in
TOL3 additional label extended dorsally to include all
laminae.
The injection in case ACy18 was largely confined to the
ventral, parvicellular division of the accessory basal nucleus (Fig. 3). As in the other two cases, the only appreciable label in nucleus accumbens was in the cell-sparse
zone adjacent to the islands of Calleja. There was also a
light zone of label in lamina III in TOL2 and TOL3. This
was largely concentrated just deep to lamina II. The light
label in nucleus accumbens in case ACy18 could be contrasted with the much more extensive label found in
ACy21L (Fig. 6, top), which had an injection placed in the
basal nucleus immediately lateral to that in ACy18 (Fig.
3).
Medial and central nuclei projections. In case ACy22L
(Figs. 3, 7, bottom) the injection involved primarily the
medial nucleus. The only ventral striatal label was found
in the olfactory tubercle (TOL2 and TOL3). This label was
most dense in lamina II, with a limited extension into the
most superficial portion of lamina III. The injection in
ACy17 (Fig. 6, bottom) was the only one to involve the
central nucleus appreciably. A light scattering of label was
found in the ventral and caudal halves of nucleus accumbens, along with light label in the deeper portions of TOL2
and TOL3 in the olfactory tubercle.
Hippocampal efferents to the nucleus accumbens
and olfactory tubercle. Figures 2, 5, and 8 depict the
placement and extent of the injections into the hippocampal formation and adjacent rhinal cortex. The wellestablished projection from the hippocampus to the nucleus accumbens was confirmed in all of the normal
animals whose injection included the subiculum (ACy12,
ACy14, ACy28). In addition, light projections to the olfactory tubercle were observed. The projections from the subiculum to the nucleus accumbens appeared to rely on the
fornix, insofar as animals in which the fornix had been
transected before the hippocampal injection was made
showed no label in nucleus accumbens. In no case was
label found in the striatum in the contralateral hemisphere.
Prominent projections to nucleus accumbens were observed in two cases with similar injections centered in the
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
353
Fig. 6. Distribution of anterograde label in ventral striatum following amino acid injections in the amygdala. The longer lines depict
fiber-like regions. Top row: Case ACy21L, showing label resulting
from an injection centered in the intermediate division of the basal
nucleus. Note that the label is most dense in the most caudal portions
of the medial division of nucleus accumbens (NASM). Sections are
presented from rostral to caudal (left to right). Middle row: Case
ACy6, illustrating anterograde label from an injection that included
the magnocellular and intermediate parts of the basal nucleus. Bottom row: Case ACy17, showing anterograde label following injection
into the central nucleus and adjacent basal nucleus. For abbreviations
see list. Scale bars ⫽ 1 mm.
rostral subiculum (ACy14, Fig. 5; ACy12, Fig. 9, top). In
both animals, the label was clearly concentrated in the
medial ventral portion of the structure, and, at most levels, this densely concentrated label was within the cytoarchitectonically distinct medial sector visible within the
nucleus accumbens in cynomolgus monkeys. Some sparse
label did appear in the lateral division of the accumbens,
but it was found largely in the medial aspect of that
division. Both cases also showed label throughout the
rostral– caudal limit of nucleus accumbens, and there was
no evidence of a gradient in this plane. In both ACy12 and
ACy14, the terminal label filled the very rostral pole of the
nucleus accumbens and extended even farther rostrally
into the most ventral portion of the caudate nucleus.
A slightly different pattern of label was observed in case
ACy28 (Fig. 9, bottom), in which an extensive injection
filled much of the caudal hippocampus and the subiculum
(Fig. 8, top). Once again, label was present throughout the
354
D.P. FRIEDMAN ET AL.
Fig. 7. Top row: Case ACy10, illustrating anterogradely transported label in the ventral striatum from an injection largely confined
to the parvicellular division of the basal nucleus. Middle row: Case
ACy20L, illustrating anterogradely transported label in the ventral
striatum from an injection largely confined to the magnocellular division of the accessory basal nucleus. Note the relatively light amount
of label in nucleus accumbens, except for the restricted zone of label in
the cell sparse region immediately lateral to the islands of Calleja.
Bottom row: Case ACy22L, showing distribution of label in the
ventral striatum following an injection into the medial nucleus. Note
the lack of ventral striatal label. The longer lines depict fiber-like
regions. For abbreviations see list. Scale bars ⫽ 1 mm.
rostral– caudal limits of nucleus accumbens, but now
nearly all of it was in the ventral one-third of the nucleus.
Furthermore, much of the label was made up of fibers, and
the density of termination appeared considerably lower
than in ACy12 and ACy14. Terminal-like label was also
present in the medial parts of the olfactory tubercle.
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
Fig. 8. Location of anterograde tracer injections in the hippocampal formation shown on standard coronal sections. Top: Center of the
injection sites in normal cases. Bottom: Cases in which the fornix was
surgically sectioned prior to tracer injection. For abbreviations see
list.
In contrast to these cases, no label was observed in the
ventral striatum when the injection was largely confined
to the dentate gyrus (case ACy25). Likewise, no striatal
label was observed in any of the cases with injections in
the subiculum or CA fields 1– 4 when the injection was
made after the fornix had been transected (cases ACyF15,
ACyF19, ARhF24, ACyF27L).
Perirhinal and entorhinal efferents to the nucleus
accumbens and olfactory tubercle. Although the pattern of entorhinal inputs to the ventral striatum was
similar to that from the subiculum, the perirhinal inputs
differed in that they terminated much more densely in the
olfactory tubercle and used a nonfornical route. In case
ERh3, in which multiple injections involved the entire
extent of the entorhinal cortex (Figs. 2, 5, 8), a dense
projection was observed throughout the rostral– caudal
extent of nucleus accumbens (Fig. 10, top). This label
appeared to be largely confined to the medial division of
the nucleus but avoided the “dorsal cone” region. Unlike
the case with subicular injections, the projection to the
olfactory tubercle was as dense as the projection to the
nucleus accumbens. Label was present throughout the
355
medial–lateral and rostral– caudal extents of the tubercle,
and, although it was most dense close to nucleus accumbens, it extended ventrally to the superficial laminae in
TOL2 and TOL3 as well. Label was also present in the
caudate nucleus, being concentrated at the ventral, medial, and dorsal edges of the most rostral part of the head
of the caudate. The ventral label appeared to be a continuation of that in nucleus accumbens. In cases ERh1 and
ERh2, the distribution of anterograde label in nucleus
accumbens and the olfactory tubercle was very similar to
that in ERh3, though less dense. These results indicate
that there is not a rostral-to-caudal topography in the
origin of these entorhinal projections.
A case with an injection involving the middle and caudal
levels of area 35 and adjacent area 36 (PRh1) resulted in
only a very light scattering of label across the most ventral
part of nucleus accumbens, whereas there was an appreciably more dense projection in the striatal portion of the
olfactory tubercle. Patches of label were also present in
the most ventral parts of the putamen and caudate nucleus, rostral to nucleus accumbens. This trend for a relative increase in olfactory tubercle label was repeated in
case ACy9, in which the injection was in the caudal limit
of area 36, with some spread into area 35, as well as
rostral TF and TH. The pattern of label was very similar
to that in PRh1; there was label throughout the striatal
portion of the olfactory tubercle and in a number of distinct patches in the ventral limits of the most rostral
regions of the putamen and caudate (Fig. 10, middle).
Only very light label extended into the most ventral portion of nucleus accumbens.
Evidence that these entorhinal and perirhinal projections used a nonfornical route came from two cases
(ARhF23 and ACyF27R, Fig. 7) in which the fornix had
been cut. The injection in case ARhF23 was placed in the
caudal part of the rhinal sulcus, and it was centered in
area 28S but also involved the most medial part of area 35.
A light, but distinct, region of label was present across the
ventral one-third of nucleus accumbens and that part of
the olfactory tubercle adjacent to nucleus accumbens (Fig.
10, bottom). A mixture of labeled fibers and terminal-like
label could also be traced rostrally in the most ventral
portions of the caudate and putamen. The lightness of
these projections compared with those in ERh3 suggests
that these regions receive parallel inputs via the fornix
and some other route.
In case ARhF27R, the injection extended ventrally from
the subiculum to involve areas 35 and 36. There was a
region of light label in the most ventral one-fourth of
nucleus accumbens, continuous with a much more distinct
region of label in the olfactory tubercle. This label was
mainly restricted to the striatal portions of TOL2 and
TOL3. Patches of label were also found in the most ventral
portions of the putamen and caudate nucleus rostral to the
nucleus accumbens, and diffuse label was present
throughout the very rostral pole of the caudate. The strong
similarities between this case and the normal case with an
injection in the perirhinal region (PRh1) suggest that most
or all of the perirhinal projections use a nonfornical route.
Retrograde tracers
Afferents to the nucleus accumbens revealed by retrograde tracers. Figure 11 depicts the location and extent of two pairs of retrograde tracer injections. Each pair
of injections was placed mediolaterally adjacent to each
356
D.P. FRIEDMAN ET AL.
Fig. 9. Distribution of anterograde label in ventral striatum following two injections centered in the subiculum and prosubiculum.
Top row: In case ACy14, the injection site was centered in the uncal
level of the subiculum, and the resulting label was concentrated in the
rostral NASM with little or no label in the TOL. Bottom row: In
contrast, the injection in case ACy28 was centered in the posterior
subiculum, and the label in the ventral striatum was in the ventral
part of the NASM and included the TOL2 and TOL3. The longer lines
depict fiber-like regions. For abbreviations see list. Scale bars ⫽ 1
mm.
other within nucleus accumbens in the same hemisphere.
In NaRh1, diamidino yellow was injected medially and
fast blue laterally. In NaRh2, the positions were reversed.
There did not appear to be any effect of this change on the
extent or distribution of retrogradely labeled neurons. The
borders of these injection sites were taken as the extent of
extracellular fluorescent dye seen under fluorescent illumination. In both cases, injections were made to clarify
the differences in inputs of the medial and lateral divisions of nucleus accumbens, and the data from both animals were remarkably congruent. To simplify the presentation, the data from animal NaRh1 will principally be
used to summarize the findings. This animal was selected
because, in this case, the two injections were at very
similar rostrocaudal levels. In both NaRh1 and NaRh2,
the injections were largely limited to the nucleus accumbens but did encroach into the dorsal olfactory tubercle. In
none of these cases was contralateral label observed in the
amygdala, hippocampal formation, or perirhinal cortex.
Amygdala. Of the two injection sites, the medial nucleus accumbens injection resulted in the greater amount
of amygdala label. This can be seen in Figures 12 and 13,
which both show two coronal sections, one from the rostral
half and the other from the caudal half of the amygdala. In
case NaRh1, after a medial nucleus accumbens injection,
the retrograde label was most dense in the basal nucleus,
with the magnocellular and parvicellular divisions containing the greater proportion of label. There was less
label in the magnocellular accessory basal nucleus and
only sparse label in the parvicellular accessory basal and
lateral nuclei. Although little or no label was observed in
the medial or central nuclei, there was a continuation of
label from the parvicellular basal nucleus into the adjacent cortical amygdaloid transition area. There was, in
addition, a rostrocaudal gradient, with the caudal amygdala containing the greater numbers of labeled cells (Fig.
12). Nevertheless, the relative distribution of label in the
various nuclei remained very similar between the rostral
and the caudal amygdala. Case NaRh2 revealed a very
similar pattern of retrograde label in the amygdala (Fig.
13), although the relatively lighter label in the magnocellular basal nucleus following a medial injection presum-
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
357
Fig. 10. Distribution of anterograde label in ventral striatum following injections centered in the rhinal cortex. Top row: A large
injection in the entorhinal cortex (case ERh3) resulted in dense label
throughout the ventral striatum. The label was most dense in the
NASM and less so in NASL. and avoided the dorsal cone region. In
contrast to labeling seen after the subicular injections, much of the
TOL was also labeled. Middle row: In case ACy9, the injection was
centered in the caudal region of perirhinal cortex. There was label
throughout the striatal portion of the TOL and only light label in the
more ventral NAS. Bottom row: In case ARhF23, the injection was in
the caudal entorhinal and perirhinal cortex in an animal in which the
fornix had been transected prior to injection. The label was very
similar to that in case ACy9 but somewhat lighter. This suggests that
most or all of the perirhinal projections use a nonfornical route. For
abbreviations see list. Scale bars ⫽ 1 mm.
ably reflects the more rostral placement of the accumbens
injection. This is consistent with the anterograde results
(e.g., cases ACy21L, ACy6, Fig. 6).
The pattern of label following a lateral nucleus accumbens injection (NaRh1, NaRh2) was similar to that after a
medial injection but considerably less dense in nearly all
sites (Figs. 12, 13). The only exceptions were the rostral
parts of the magnocellular basal nucleus and the parvicellular accessory basal nucleus. Both of these areas contained numbers of labeled cells comparable to those found
after a medial nucleus accumbens injection. Little or no
label was found in the medial, central, or lateral nuclei. In
no case could we detect a contralateral projection from the
amygdala to nucleus accumbens.
Hippocampal formation. Retrograde label, resulting
primarily from the medial injection, was visible through-
out the rostral two-thirds of the hippocampal formation
(Figs. 14, 15). In both NaRh1 and NaRh2, the overall
distribution of label was very similar following medial or
lateral injections, but the label was consistently more
dense in the former case. After a medial injection (all
cases), labeled neurons were present at the most rostral,
genual portion of the hippocampus in fields CA1 and CA1⬘,
the subiculum, and the prosubiculum. The hippocampal–
amygdaloid transition area was labeled by both injections
(data not shown). In case NaRh1, there was only modest
label in the ventral part of CA1 at the level of the uncus,
whereas the subiculum had the most dense label (Fig. 14).
This subicular label was concentrated in the pyramidal
cells in the middle layer. The prosubiculum also contained
labeled cells in the same layer but at a lower density.
Pyramidal cells in the deep layers of the parasubiculum
358
D.P. FRIEDMAN ET AL.
Fig. 11. Injections of retrograde tracers were made in two monkeys,
with the location of the injection sites of the fluorescent tracers shown on
a rostral–caudal series of coronal sections (A–D). Top row: Case NaRh1
received a NAS medial injection of diamidino yellow and a lateral
injection of fast blue. Bottom row: Case NaRh2 received an NAS
medial injection of fast blue and a lateral injection of diamidino
yellow. Note that the injection sites were centered in nucleus accumbens, with some encroachment into dorsal olfactory tubercle. For
abbreviations see list. Scale bars ⫽ 2 mm.
also contained moderate amounts of label from both injections, but again the medial injection led to the more dense
labeling. More surprisingly, field CA3 showed numerous
labeled cells (Figs. 14, 16) but only in the uncal compartment. This CA3 label was observed in cases with both
medial and lateral injections in nucleus accumbens. A
very similar pattern was observed in NaRh2, except that
far fewer labeled cells were observed in the uncal part of
CA3. This may, in part, reflect the more rostral placement
of the medial injection.
At more caudal levels of the hippocampal formation,
retrograde label was still clearly visible, being found in the
CA1 field and in the prosubiculum, subiculum, and parasubiculum (Figs. 14, 15). At all of these levels, the CA1
label was light, and at no level could label be found in the
presubiculum.
Perirhinal and entorhinal cortices. Neurons
throughout the entire extent of entorhinal cortex were
labeled from both the medial and the lateral injections in
case NaRh1, but, in some regions, there was a clear difference in the density of this label, with the medial injection resulting in appreciably more label (Figs. 12, 14).
Thus, although there were relatively small differences in
the numbers of labeled neurons in area 28S from both
lateral and medial injection sites, the density of labeling
in area 28M was much greater after the medial injection.
After both medial and lateral injections, a light distribution of label was found in areas 35 and 36 of the perirhinal
cortex, but, unlike the case in some divisions of the entorhinal cortex, there was no consistent difference between
medial and lateral injection sites. In all fields, the projections principally originated in layer V (Figs. 14, 17), with
only occasional labeled cells in other layers. Thus, in areas
35 and 36, a few cells in layer III were labeled in addition
to those in layer V. In case NaRh2 (Figs. 13, 15), the
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
Fig. 12.
Retrograde label in the amygdala after injections of
tracers in the medial (left) and lateral (right) nucleus accumbens.
The label in case NaRh1, which is depicted on representative sections
from midrostral (top) and midcaudal (bottom) levels of the amygdala,
was more dense after the medial injections than after the lateral
injections. Right: The lateral accumbens injection resulted in light
label within the basal and accessory basal nuclei. Left: In contrast, the
medial accumbens injection resulted in much more dense label within
the basal nuclei and cortical amygdaloid transition area. Within the
accessory basal nucleus, the magnocellular (dorsal) division contained
the majority of labeled cells. The deep layers of the entorhinal and
perirhinal cortex were labeled throughout, with the medial injection
resulting in the more dense label. Arrows depict area borders. For
abbreviations see list.
pattern of retrograde label was, once again, very similar to
that in case NaRh1.
DISCUSSION
Anterograde and retrograde tracer studies showed that
projections to the ventral striatum from the amygdaloid
complex, hippocampal formation, and entorhinal cortex
overlap within the medial and ventral portions of the
nucleus accumbens and the adjacent olfactory tubercle
(Fig. 18). Both tracer techniques also showed that these
projections did not cross to the contralateral hemisphere.
By reference to normal cases showing regions of calbindin
staining, it was possible to confirm that the area of overlap
was largely confined to the calbindin-negative, or shell,
359
Fig. 13.
Retrograde label in the amygdala after injections of
tracers in the medial (left) and lateral (right) nucleus accumbens.
The label in case NaRh2 is shown on representative sections from the
midrostral (top) and midcaudal (bottom) levels of the amygdala. Although the amygdala label was more dense after the medial injections
(left) than after the lateral injections (right) in nucleus accumbens,
this difference was much clearer in the middle and caudal levels of the
amygdala. The distribution of label is very similar to that seen in case
NaRh1. Arrows depict area borders. For abbreviations see list.
region of the nucleus accumbens. The strongest projections from the amygdala arose in the magnocellular, parvicellular, and intermediate divisions of the basal nucleus.
The hippocampal projections arose primarily in the subiculum and prosubiculum, with a somewhat smaller contribution from field CA1 and uncal CA3. Progressively
more lateral portions of entorhinal and perirhinal cortex
had diminishing projections to the shell region, but these
projected to the olfactory tubercle in all cases (Fig. 18).
Although identification of these limbic projections relied
on both anterograde and retrograde tracers, there is reason to believe that the retrograde tracers were the more
sensitive (e.g., inputs from the lateral nucleus of the
amygdala to nucleus accumbens). For this reason, the
absence of label as revealed by amino acids cannot be
taken as proof that a very light projection does not exist.
Relationship to previous findings
Amygdala efferents. In agreement with other studies
(Russchen et al., 1985; Fudge et al., 2002), our findings
indicate that the basal nuclei provide the majority of the
360
Fig. 14. Retrograde label in the hippocampal formation after injections of tracers in the medial (left) and lateral (right) nucleus accumbens. The label in case NaRh1 is shown on representative sections taken
from the uncal (top) and midcaudal (bottom) levels of the hippocampal
formation. The label was considerably more dense after the medial injection than after the lateral injection. Right: The lateral injection resulted in light label in the uncal portion of the hippocampus in fields CA1
and CA3. At this level (top), there was also very light label in the
subicular regions and the adjacent entorhinal cortex and perirhinal
cortex. The light label in the subicular regions continued into more
caudal hippocampal levels (bottom). Left: At more rostral levels (top), the
medial accumbens injection resulted in dense label in the uncal ammonic
subfields and in CA1 in the main body. The prosubiculum, subiculum,
and parasubiculum and the adjacent entorhinal cortex also had extensive label. The subicular label persisted at more caudal levels (lower).
Arrows depict area borders. For abbreviations see list.
amygdala projections to the ventral striatum. The projections from the magnocellular and intermediate division of
the basal nucleus terminated preferentially in the medial,
or shell, region of the nucleus accumbens, as well as in the
adjacent olfactory tubercle. The parvicellular portion of
the basal nucleus, especially its more dorsal aspects, also
projected densely upon nucleus accumbens. The parvicellular projection, however, included not only the shell but
also the immediately adjacent portion of the lateral division, or core, of the nucleus accumbens. Whereas Russchen et al. (1985) described a similar termination pattern
for the parvicellular portion of the basal nucleus, the
present results suggest a more limited distribution of projections from the magnocellular and intermediate basal
nucleus than was reported previously. Indeed, our anterograde and retrograde data support each other, indicating
that the caudal magnocellular and intermediate basal nuclei have much more dense inputs to the shell than to the
core. Finally, the retrograde label provided evidence of a
significant input from the cortical amygdaloid transition
area, with much lighter projections from the lateral nu-
D.P. FRIEDMAN ET AL.
Fig. 15. Retrograde label in the hippocampal formation after injections of tracers in the medial (left) and lateral (right) nucleus
accumbens. The label in case NaRh2 is shown on representative
sections taken from the uncal (upper) and midcaudal (lower) levels of
the hippocampal formation. The label was appreciably more dense
after the medial injection than after the lateral injection in nucleus
accumbens. Right: The lateral injection resulted in very light label in
field CA1 and the adjacent prosubiculum, the subiculum, and the
entorhinal and perirhinal cortices. Left: The medial injection led to
appreciable labeling in field CA1, the prosubiculum, and the subiculum as well as in the parasubiculum and adjacent entorhinal and
perirhinal cortices. The label in the uncal part of CA3 was much
lighter than that in case NaRh1. Arrows depict area borders. For
abbreviations see list.
cleus, central nucleus, and medial nucleus to the medial
nucleus accumbens.
Evidence was found for a relatively lighter projection
from the accessory basal nucleus with a different pattern
of termination. Terminal-like label was largely confined to
the most medial striatal region, i.e., immediately lateral to
the islands of Calleja. This projection appeared to derive
primarily from the magnocellular rather than the parvicellular part of the accessory basal nucleus. An even more
marked difference between the magnocellular and the
parvicellular projections was reported by Fudge et al.
(2002). Unlike results from the present study, evidence
from retrograde tracers indicated quite dense projections
from the magnocellular accessory basal nucleus to a much
wider extent of the ventromedial striatum (Fudge et al.,
2002). This was not observed in any of the three cases with
amino acid injections placed in different parts of the accessory basal nucleus (two in the magnocellular region);
these all showed very restricted striatal label. Similarly,
Russchen et al. (1985) reported two cases with accessory
basal injections and one with an injection in the amygdalohippocampal area that all showed the same termination
pattern as that observed in the present study, i.e., only to
the most medial nucleus accumbens.
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
Fig. 16. Photomicrograph showing retrogradely labeled cells in
the uncal part of CA3 in the left hemisphere after an injection of
diamidino yellow into the medial nucleus accumbens (case NaRh1).
Scale bar ⫽ 500 ␮m.
Fig. 17. Darkfield photomicrograph of the left hemisphere in case
NaRh4, showing retrograde label in the deeper layers of the entorhinal cortex (areas 28S and 28I). Area 28S is in the upper bank of the
rhinal sulcus. The injection of fast blue was centered in the medial
nucleus accumbens. The injection site involved the olfactory tubercle,
and this presumably accounts for the label in the adjacent perirhinal
cortex. Scale bar ⫽ 1 mm.
The present retrograde tracer studies also indicated
that there is a rostrocaudal gradient in the projections
from the amygdala, with the more rostral aspects of the
amygdala tending to project more evenly across the shell
and core. Our data suggest that the rostral portions of the
magnocellular basal nuclei may even send a predominant
portion of their projections to the core rather than the
shell. A similar change in the rostrocaudal pattern of
amygdala efferents has been described for the rat brain
(McDonald, 1991; Brog et al., 1993; Wright et al., 1996). A
slightly different rostrocaudal caudal gradient was found
in the one other study to use retrograde tracers in the
macaque brain to analyze these inputs (Fudge et al.,
2002). The lightest inputs to the core and shell arose from
the rostral amygdala, as in the present study, but the
relative pattern of inputs to the core and shell regions did
361
not appear to vary with rostrocaudal position within the
amygdala.
Although all of the basal amygdala nuclei contribute to
these ventral striatal projections, the inputs from the lateral, central, cortical, and medial nuclei appeared very
sparse. Evidence for this came from both anterograde and
retrograde tracers. These findings appear to confirm those
of Russchen et al. (1985), who also reported that, after
amino acid injections placed in these nuclei, there was
virtually no label in the ventral striatum, although the
cortical nucleus projected to the olfactory tubercle. Again,
in a study using retrograde tracers (Fudge et al., 2002),
most of the injections placed in nucleus accumbens resulted in little or no label in these same amygdala nuclei
(Fudge et al., 2002). However, a retrograde tracer involving the dorsomedial shell of nucleus accumbens (case 82)
resulted in numerous labeled cells in the medial amygdala
nucleus, the medial portion of the central nucleus, and the
periamydaloid cortex (Fudge et al., 2002). These dense
inputs from the superficial amygdala nuclei to the dorsomedial shell are very interesting, in that they were not
revealed by retrograde tracers or by anterograde tracers
in our study. Similarly, Russchen et al. (1985) did not
observe these projections when using anterograde tracers.
This may reflect a species difference (M. fascicularis vs. M.
nemestrina), or it may reflect the presence of a distinct
subregion in the caudal portion of the dorsal shell of nucleus accumbens that lies close to the bed nucleus of the
stria terminalis.
The amygdala–striatal projections showed evidence of a
coarse topography in spite of the concentration of projections in the medial and ventral parts of nucleus accumbens. The clearest example concerned the projections from
the accessory basal nucleus to the cell-sparse portion of
the nucleus accumbens immediately lateral to the islands
of Calleja. This complemented the projections from the
basal nucleus, which terminated throughout the rest of
the medial division of the nucleus accumbens but appeared to be absent from this most medial region of the
nucleus accumbens. A similar complementary pattern was
noted by Russchen et al. (1985) but not by Fudge et al.
(2002). A different complementary pattern was, however,
observed by Fudge et al. (2002), who found that the superficial nuclei of the amygdala project to the dorsomedial
shell, whereas the inputs from the basal nucleus avoid
this region even though they have dense inputs to the rest
of the shell. In our study, we also found that the inputs
from the basal nucleus are often appreciably lighter in the
most dorsal part of the shell region.
Hippocampal efferents. Many of the hippocampal
projections to the ventral striatum arose from the subiculum, and evidence for this was found in both the anterograde and the retrograde tracer studies. These subicular
projections principally arose from the rostral and midhippocampus, and this rostrocaudal gradient is consistent
with a degeneration study concerning this projection (Siegel et al., 1975). Although the findings from the retrograde
tracers helped to confirm that the principal inputs were to
the shell-like region of nucleus accumbens, they also indicated that the source of these hippocampal inputs is not
restricted to the subicular complex. Thus, although labeled pyramidal cells were found in the midlayers of the
prosubiculum and subiculum, labeled cells were also
found in the adjacent CA1 field and in the deep layers of
the parasubiculum. The presubiculum did not contribute
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D.P. FRIEDMAN ET AL.
Fig. 18. Diagram of the route and termination of projections to
nucleus accumbens from the different amygdala nuclei (left) and from
the hippocampal formation and parahippocampal cortices (right).
The width of the lines reflects the density of the projections as determined by anterograde and retrograde tracers. Note the parallel projections from the entorhinal cortex that use both fornical and nonfornical routes and the light projection from ABmc and ABpc to the cell
sparse region at the medial border of NASM. Evidence for a more
diffuse projection from AB was presented by Fudge et al. (2002). Note
also that the projections from the rostral amygdala may have a more
even distribution across the medial and lateral nucleus accumbens.
Finally, the projection from the parasubiculum carries an asterisk,
because there are incomplete data to confirm the route. For abbreviations see list.
to this projection. The additional contribution from cells in
the adjacent portion of CA1 is also found for other hippocampal projections (Aggleton et al., 1986; Carmichael
and Price, 1995; Blatt and Rosene, 1998). More remakable, however, was the finding of labeled cells in the uncal
portion of CA3. In fact, there is evidence that uncal CA3
projects to the medial orbital prefrontal cortex (Carmichael and Price, 1995) and also receives a direct input
from the accessory basal nucleus of the amygdala (Saunders et al., 1988). It is therefore less surprising that this
region may be directly connected with another region outside the hippocampus. At the same time, it will be necessary to preclude any contribution from fibers of passage.
The subicular projections terminated throughout the
medial and ventral extent of the nucleus accumbens as
well as the adjacent portions of the most ventral, rostral
caudate nucleus. Lateral to the subicular complex, the
pattern of striatal projections showed a gradual change.
Thus, whereas the subiculum projects principally to nucleus accumbens, the entorhinal cortex projects both to
nucleus accumbens and to the olfactory tubercle, and the
perirhinal cortex projects principally to the olfactory tubercle. This transition is continued more laterally as area
TEav projects to the olfactory tubercle, but not the nucleus
accumbens, whereas TEad projects to neither (Cheng et
al., 1997). This shift is paralleled by a change in the routes
taken by these projections; the subicular projections depend on the fornix, whereas those from the entorhinal and
perirhinal cortices increasingly appear to use nonfornical
routes. The presence of retrogradely labelled cells in the
perirhinal cortex following the injection of fluorescent
tracers into nucleus accumbens probably reflected a small
amount of spread into the dorsal olfactory tubercle. The
subicular and entorhinal inputs to the nucleus accumbens
did not show a rostral– caudal gradient within the nucleus
accumbens. This contrasts with the inputs from the amygdala, which were lightest in the rostral nucleus accumbens.
Overlap of amygdala and hippocampal inputs. The
overlap of amygdala and hippocampal (subicular) projections within the medial–ventral (shell-like) portion fits a
more general pattern involving other inputs to the ventral
striatum. Thus, within the prefrontal cortex in monkeys,
it is the medial prefrontal and anterior cingulate regions
(areas 32, 25, 24a, 24b, 14) that provide projections to the
medial, shell-like portion of nucleus accumbens (Kunishio
and Haber, 1994; Haber et al., 1995; Chiba et al., 2001).
The same set of prefrontal areas provides some of the few
cortical sites for overlapping projections from the amygdala and hippocampus (Rosene and Van Hoesen, 1977;
Amaral and Price, 1984; Amaral et al., 1992; Ongur and
Price, 2000). Similarly, the shell area receives projections
from the thalamus, but these arise only from the parafascicular nucleus and from midline nuclei, including reuniens and paraventricularis (Gimenez-Amaya et al., 1995).
These same midline thalamic nuclei are the only sites of
overlap for the amygdala and the subicular projections to
the thalamus (Aggleton and Mishkin, 1984; Aggleton et
al., 1986). The entorhinal cortex provides an intriguing
addition to this pattern, in that it receives overlapping
information from the amygdala and hippocampus (Saunders and Rosene, 1988), and it projects much more heavily
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
to the medial than to the lateral division of nucleus accumbens (Fig. 15). Thus the shell part of nucleus accumbens represents a potential site of convergence for direct
amygdala and hippocampal projections and a site of termination for those limited other sites that also appear to
receive convergent information from these two key limbic
structures.
Cross-species comparisons
The shell and core have been most thoroughly studied in
the rat brain, raising the question of whether there is
cross-species agreement in the pattern of limbic innervations across the shell– core division. There are overall similarities in the patterns of projections, but the details
differ in a number of important ways. In both the rat and
the macaque monkey, it is the basal nucleus of the amygdala that provides the main source of inputs (Russchen et
al., 1985; McDonald, 1991; Brog et al., 1993). The amygdala projections in the rat also show a similar rostrocaudal
transition, with more caudal portions of the basal and
accessory basal nucleus terminating in the shell, and more
rostral portions terminating in both the shell and the core
(McDonald, 1991; Brog et al., 1993; Wright et al., 1996).
Interestingly, the rostral amygdala projections to the core
of the rat are often concentrated in calbindin-negative
“zones” (Wright et al., 1996). These zones seem less evident in the primate brain (Meredith et al., 1995), and
there was no evidence of any discrete clustering of amygdala projections in the lateral division of the nucleus accumbens in our study or in that of Fudge et al. (2002). In
the rat, projections from the medial entorhinal cortex terminate in the shell, and those from the lateral entorhinal
cortex terminate in both the shell and the core (Brog et al.,
1993). A similar pattern emerged from the retrograde
tracer experiments. Finally, the perirhinal cortex projects
to the shell in the rat (Brog et al., 1993), and, in the
monkey, the perirhinal cortex has a light input to that
part of the ventral nucleus accumbens that is in the medial, shell-like division.
The shell of nucleus accumbens has been subdivided in
the rat into medial, lateral, and ventral portions on the
basis of their connectional properties (Groenewegen et al.,
1999a,b). From our results, the only division that could be
made concerned the most medial strip of nucleus accumbens, which selectively receives inputs from the accessory
basal nucleus of the amygdala. In spite of this, there was
no evidence of discrete neuronal ensembles within the
shell region as has been described in the rat (Groenewegen et al., 1999a,b). Other species differences concerned
the lack of any crossed projections in the macaque brain.
This contrasts with the rat, in which both the hippocampus and, especially, the amygdala (McDonald, 1991; Brog
et al., 1993) provide lighter, but appreciable, inputs to the
contralateral nucleus accumbens. In the rat, the projections from the subiculum and field CA1 terminate in both
the shell and the core (Brog et al., 1993), but, in the
macaque, these connections appear to be more closely
associated with just the shell-like region. Although there
is a rostral– caudal gradient in these projections in both
species, it is qualitatively different. In the rat, the septal
pole of the hippocampus may project preferentially to the
lateral nucleus accumbens, whereas the more ventral and
temporal hippocampus projects to medial nucleus accumbens (Groenewegen et al., 1987). In the monkey, the
rostral– caudal gradient concerns a change in the density
363
of projections, not in their termination sites. Thus the
rostral hippocampus (equivalent to the ventral hippocampus of the rat) provides the heaviest inputs to the ventral
striatum.
Functional implications
The inputs from the hippocampus to the ventral striatum showed a rostral– caudal gradient in their sites of
origin, with more numerous inputs arising from the rostral hippocampus. Other hippocampal efferents also show
a similar rostral– caudal gradient from within the subiculum and CA1, e.g., those to the amygdala, thalamus, and
medial orbital frontal cortex (Aggleton, 1986; Aggleton et
al., 1986; Carmichael and Price, 1995; Blatt and Rosene,
1998; Ongur and Price, 2000). These data point to a functional differentiation within rostral– caudal levels of the
hippocampus and, possibly, to a functional link between
these particular hippocampal efferents. Evidence for functional differentiation within different levels of the hippocampus has been found both in the rat (Moser et al.,
1995; Moser and Moser, 1998) and in the monkey (Colombo
et al., 1998). The results of a single-unit recording study in
awake, behaving monkeys (Colombo et al., 1998) suggest
that movement-related and spatial aspects of hippocampal function may be primarily controlled, respectively, by
the rostral and caudal regions of the hippocampus. The
notion that the more rostral hippocampal regions may be
more important for directing or coding movement in space
very readily accords with the finding of more inputs from
the rostral hippocampus to the ventral striatum (Mogenson et al., 1980). There are also data from imaging studies
that indicate functional differences within the rostrocaudal extent of the human hippocampus (Schacter and Wagner, 1999; Maguire et al. 2000), so there is added interest
in anatomical connections that might underlie these differences.
A novel feature of the present study was the comparison
of those efferents from the hippocampal formation that
use fornical or nonfornical routes. This is of interest in
view of the growing evidence that fornix damage is sufficient to induce anterograde amnesia (Gaffan and Gaffan,
1991; McMackin et al., 1995; Aggleton et al., 2000). Although efferents from the hippocampus proper and subiculum exclusively use the fornix, those from the entorhinal
cortex appear to use both fornical and nonfornical routes.
The perirhinal cortex, which has some mnemonic functions that are independent of the hippocampus (Murray,
1982; Brown, 1996; Suzuki, 1996; Brown and Aggleton,
2001), uses only nonfornical routes. This reliance on nonfornical routes is consistent with evidence that the cognitive effects of fornix lesions can differ qualitatively from
those of perirhinal lesions (Gaffan, 1994; Ennaceur et al.,
1996; Bussey et al., 1999).
There is much interest in the role of these limbic inputs
to the nucleus accumbens, but direct testing of their importance using lesions requires crossed-hemispheric disconnection studies. Such experiments have not been conducted with monkeys, but disconnection experiments with
rats have helped to confirm amygdala–ventral striatal
interactions in reward-related processes (Everitt and Robbins, 1992). These amygdala–striatal interactions appear
to extend to the learning of cues associated with drug
administration and so have implications for drug addiction (Everitt et al., 2000). This may relate to evidence that
both the amygdala and the ventral striatum contain high
364
D.P. FRIEDMAN ET AL.
densities of mu-opiod receptors in monkeys (Daunais et
al., 2001). Other evidence for a role in certain rewardrelated behaviors comes from the finding that both the
central nucleus of the amygdala and the nucleus accumbens core, but not the basolateral nucleus or the shell, are
important for Pavlovian influences on instrumental-like
responding (Parkinson et al., 2000; Hall et al., 2001). In
addition to a role in reward mechanisms, there is also
evidence that the inputs from the basolateral amygdala to
the nucleus accumbens may modulate glucocorticoid effects on memory consolidation that require the integrity of
the hippocampus (Roozendaal et al., 2001).
Finally, single-unit recording studies in rats (Mulder et
al., 1998; Groenewegen et al., 1999a) have cast light on the
interaction of amygdala and hippocampal projections
within the nucleus accumbens, revealing an intriguing
temporal relationship in which prior amygdala activation
of the nucleus accumbens can enhance a hippocampal
response, whereas a reversal of the order of stimulation
can lead to a depression of the amygdala response. This
interaction depends, in part, on dopaminergic mechanisms (Floresco et al., 2001). The notion that these inputs
can “gate” each other is important for understanding the
ventral striatum, and the present anatomical study
clearly shows that the most likely region for such interaction in the primate ventral striatum is in the medial or
shell-like portion of nucleus accumbens.
ACKNOWLEDGMENTS
The authors are grateful for the support and assistance
of L. Awcock, J. Erichsen, M. Mishkin, R. Moore, and S.
Vinsant.
LITERATURE CITED
Aggleton JP. 1985. X-ray localization of limbic structures in the cynomolgus monkey (Macaca fascicularis). J Neurosci Methods 14:101–108.
Aggleton JP. 1986. A description of the amygdalo-hippocampal interconnections in the macaque monkey. Exp Brain Res 64:512–526
Aggleton JP, Mishkin M. 1984. Projections of the amygdala to the thalamus in the cynomolgus monkey. J Comp Neurol 222:56 – 68.
Aggleton JP, Desimone R, Mishkin M. 1986. The origin, course, and termination of the hippocampo-thalamic projections in the macaque.
J Comp Neurol 243:409 – 421.
Aggleton JP, Friedman DP, Mishkin M. 1987. A comparison between the
connections of the amygdala and hippocampus with the basal forebrain
in the macaque. Exp Brain Res 67:556 –568.
Aggleton JP, McMackin D, Carpenter K, Hornak J, Kapur N, Halpin S,
Wiles CM, Kamel H, Brennan P, Carton S, Gaffan D. 2000. Differential
cognitive effects of colloid cysts in the third ventricle that spare or
compromise the fornix. Brain 123:800 – 815.
Amaral D, Price JL. 1984. Amygdalo-cortical projections in the monkey
(Macaca fascicularis). J Comp Neurol 230:465– 496.
Amaral D, Insausti R, Cowan WM. 1987. The entorhinal cortex of the
monkey: I. Cytoarchitectonic organization. J Comp Neurol 264:326 –
355.
Amaral DG, Price JL, Pitkanen A, Carmichael ST. 1992. Anatomical organization of the primate amygdaloid complex. In: Aggleton JP, editor.
The amygdala: neurobiological aspects of emotion, memory and mental
dysfunction. New York: Wiley-Liss. p 1– 66.
Bachevalier J, Saunders RC, Mishkin M. 1985. Visual recognition in monkeys: effects of transection of fornix. Exp Brain Res 57:547–553.
Blatt GJ, Rosene DL. 1998. Organization of direct hippocampal efferent
projections to the cerebral cortex of the rhesus monkey: projections
from CA1, prosubiculum, and subiculum to the temporal lobe. J Comp
Neurol 392:92–114.
Brauer K, Hauser M, Hartig W, Arendt T. 2000. The core-shell dichotomy
of nucleus accumbens in the rhesus monkey as revealed by double-
immunofluorescence and morphology of cholinergic interneurons.
Brain Res 858:151–162.
Brodman K. 1909. Vergleichende Lakalisationslehre der Grosshirnrinde:
in ihren Prinzipien dargestellt anf Grund des Zellenbaues. Leipzig:
Verlag von Johann Ambrosisus Barth.
Brog JS, Salyapongse A, Deutch AY, Zahm DS. 1993. The patterns of
afferent innervation of the core and shell of the accumbens” part of the
rat ventral striatum: immunohistochemical detection of retrogradely
transported fluoro-gold. J Comp Neurol 338:255–278.
Brown MW. 1996. Neuronal responses and recognition memory. Semin
Neurosci 8:23–32.
Brown MW, Aggleton JP. 2001. Recognition memory: what are the roles of
the perirhinal cortex and hippocampus? Nat Rev Neurosci 2:51– 61.
Bussey TJ, Muir JL, Aggleton JP. 1999. Functionally dissociating aspects
of event memory: the effects of combined perirhinal and postrhinal
lesions on object and place memory in the rat. J Neurosci 19:495–503.
Carmichael ST, Price JL. 1995. Limbic connections of the orbital and
medial prefrontal cortex in macaque monkeys. J Comp Neurol 363:
615– 641.
Cheng K, Saleem KS, Tanaka K. 1997. Organization of corticostriatal and
corticoamygdalar projections arising from the anterior inferotemporal
area TE of the macaque monkey: a Phaseolus vulgaris leucoagglutin
study. J Neurosci 17:7902–7925.
Chiba T, Kayahara T, Nakano K. 2001. Efferent projections of infralimbic
and prelimbic areas of the medial prefrontal cortex in the Japanese
monkey, Macaca fuscata. Brain Res 888:83–101.
Colombo M, Fernandez T, Nakamura K, Gross CG. 1998. Functional differentiation along the anterior–posterior axis of the hippocampus in
monkeys. J Neurophysiol 80:1002–1005.
Crosby EC, Humphrey T. 1941. Studies of the vertebrate telencephalon. II
The nuclear pattern of the anterior olfactory nucleus, tuberculum olfactorium and the amygdaloid complex in adult man. J Comp Neurol
74:309 –352.
Daitz HM, Powell TPS. 1954. Studies of the connexions of the fornix
system. J Neurol Neurosurg Psychiatr 17:75– 82.
Daunais JB, Letchworth SR, Sim-Sellet LJ, Smith HR, Childers SR, Porrino LJ. 2001. Functional and anatomical localization of mu opiod
receptors in the striatum, amygdala, and extended amygdala of the
nonhuman primate. J Comp Neurol 433:471– 485.
Ennaceur A, Neave NJ, Aggleton JP. 1996. Neurotoxic lesions of the
perirhinal cortex do not mimic the behavioural effects of fornix transection in the rat. Behav Brain Res 80:9 –25.
Everitt BJ, Robbins TW. 1992. Amygdala–ventral striatal interactions and
reward related processes. In: Aggleton JP, editor. The amygdala: neurobiological aspects of emotion, memory and mental dysfunction. New
York: Wiley-Liss. p 401– 429.
Everitt BJ, Cardinal RN, Hall J, Parkinson JA, Robbins TW. 2000. Differential involvement of amygdala subsystems in appetitive conditioning
and drug addiction. In: Aggleton JP, editor. The amygdala: a functional
analysis. New York: Oxford University Press. p 353–390.
Floresco SB, Blaha CD, Yang CR, Phillips AG. 2001. Modulation of hippocampal and amygdala-evoked activity of nucleus accumbens neurons
by dopamine: Cellular mechanisms of input selection. J Neurosci 21:
2851–2860.
Friedman DP, Porrino LJ, Vinsant S. 1992. Anatomical analysis of the
ventral striatum in the macaque monkey. Soc Neurosci Abstr 18:307.
Fudge JL, Kunishio K, Walsh P, Richard C, Haber SN. 2002. Amygdaloid
projections to ventromedial striatal subterritories in the primate. Neuroscience 110:257–275.
Gaffan D. 1994. Dissociated effects of perirhinal cortex ablation, fornix
transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe. Exp Brain Res 99:411– 422.
Gaffan D, Gaffan EA. 1991. Amnesia in man following transection of the
fornix. Brain 114:2611–2618.
Gimenez-Amaya JM, McFarland NR, de las Heras S, Haber SN. 1995. The
organization of thalamic projections to the ventral striatum in the
primate. J Comp Neurol 354:127–149.
Groenewegen HJ, Vermeulen-Van der Zee E, te Kortschot A, Witter MP.
1987. Organization of the projections from the subiculum to the ventral
striatum in the rat. A study using anterograde transport of Phaseolus
vulgaris leucoagglutin. Neuroscience 23:103–120.
Groenewegen HJ, Berendse HW, Meredith GE, Haber SN, Voorn P,
Wolters JG, Lohman AHM. 1991. Functional anatomy of the ventral,
limbic system-innervated striatum. In: Willner P, Scheel-Kruger J,
MEDIAL TEMPORAL PROJECTIONS TO VENTRAL STRIATUM
editors. The mesolimbic dopamine system: from motivation to action.
London: John Wiley and Sons Ltd. p 19 – 60.
Groenewegen HJ, Mulder AB, Beijer AVJ, Wright CI, Lopes da Silva FH,
Pennartz CMA. 1999a. Hippocampal and amygdaloid interactions in
the nucleus accumbens. Psychobiology 27:149 –164.
Groenewegen HJ, Wright CI, Beijer AVJ, Voorn P. 1999b. Convergence and
segregation of ventral striatal inputs and outputs. Ann NY Acad Sci
877:49 – 63.
Haber SN, Fudge JL. 1997. The interface between dopamine neurons and
the amgydala: implications for schizophrenia. Schiz Bull 23:471– 482.
Haber SN, Lynd-Balta E, Spooren WPTM. 1994. Integrative aspects of
basal ganglia circuitry. In: Percheron G, McKenzie JS, Feger J, editor.
The basal ganglia IV. New York: Plenum Press. p 71– 80.
Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E. 1995. The orbital and
medial prefrontal circuit through the primate basal ganglia. J Neurosci
15:4851– 4867.
Hall J, Parkinson JA, Connor TM, Dickinson A, Everitt BJ. 2001. Involvement of the central nucleus of the amygdala and nucleus accumbens
core in mediating Pavlovian influences on instrumental behaviour. Eur
J Neurosci 13:1984 –1992.
Heimer L. 1978. The olfactory cortex and the ventral striatum. In: Livinston KE, Hornykiewicz O, editor. Limbic mechanisms. New York: Plenum Press. p 95–187.
Heimer L, Switzer RD, Van Hoesen GW. 1982. Ventral striatum and
ventral pallidum. Components of the motor system? Trends Neurosci
5:83– 87.
Keizer K, Kuypers HGJM, Huisman AM, Dann O. 1983. Diamidino yellow
dihydrochloride (DY.2HCl); a new fluorescent retrograde neuronal
tracer which migrates only very slowly out of the cell. Exp Brain Res
51:179 –191.
Krettek JE, Price JL. 1977. Projections of the amygdaloid complex to the
cerebral cortex and thalamus in the rat and cat. J Comp Neurol 172:
687–722.
Kunishio K, Haber SN. 1994. Primate cingulostriatal projection: limbic
striatal versus sensorimotor striatal input. J Comp Neurol 350:337–
356.
Kuypers HGJM, Bentivoglio M, Catsman-Berrevoets CE, Bharos AT. 1980.
Double retrograde neuronal labeling through divergent axon collaterals using two fluorescent tracers with the same excitation wavelength
which label different features of the cell. Exp Brain Res 40:383–392.
Lorente de No R. 1934. Studies on the structure of the cerebral cortex. II
continuations of the study of the ammonic system. J Psychol Neurol
46:113–177.
Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RSJ, Frith CD. 2000 Navigation-related structural change in the
hippocampi and taxi drivers. Proc Natl Acad Sci USA 97:4398 – 4403.
Martin LJ, Hadfield MG, Dellovade TL, Price DL. 1991. The striatal mosaic
in primates: patterns of neuropeptide immunoreactivity differentiate
the ventral striatum from the dorsal striatum. Neuroscience 43:397–
417.
McDonald AJ. 1991. Topographic organization of amygdaloid projections to
the caudate, putamen, nucleus accumbens, and related striatal-like
areas of the rat brain. Neuroscience 44:15–33.
McMackin DJ, Cochrane J, Anslow P, Gaffan D. 1995. Correlation of fornix
damage with memory impairment in six cases of colloid cyst removal.
Acta Neurochir 135:12–18.
Meibach RC, Siegel A. 1977. Thalamic projections of the hippocampal
formation: evidence for an alternative pathway involving the internal
capsule. Brain Res 134:1–12.
Meredith GE, Pattiselanno A, Groenewegen HJ, Haber SN. 1995. Shell and
core in monkey and human identified with antibodies to calbindinD28k. J Comp Neurol 365:628 – 639.
Mogenson GJ, Jones DL, Yim CY. 1980. From motivation to action: functional interface between the limbic system and the motor system. Progr
Neurobiol 14:69 –97.
Moser MB, Moser EI. 1998. Functional differentiation in the hippocampus.
Hippocampus 8:608 – 619.
Moser MB, Moser EI, Forrest E, Morris RG. 1995. Spatial learning with a
365
minislab in the dorsal hippocampus. Proc Natl Acad Sci USA 92:9697–
9701.
Mulder AB, Hodenpijl MG, Lopes da Silva FH. 1998. Electrophysiology of
the hippocampal and amygdaloid projections to the nucleus accumbens
of the rat: convergence, segregation, and interaction of inputs. J Neurosci 18:5095–5102.
Murray EA. 1992. Medial temporal lobe structures contributing to recognition memory: the amygdaloid complex versus the rhinal cortex. In:
Aggleton JP, editor. The amygdala: neurobiological aspects of emotion,
memory, and mental dysfunction. New York: Wiley-Liss. p 453– 470.
Nauta WJH. 1961. Fibre degeneration following lesions of the amygdaloid
complex in the monkey. J Anat 95:515–532.
Ongur D, Price JL. 2000. The organization of networks within the orbital
and medial prefrontal cortex of rats, monkeys and humans. Cereb
Cortex 10:206 –219.
Parkinson JA, Robbins TW, Everitt BJ. 2000. Dissociable roles of the
central and basolateral amygdala in appetitive emotional learning. Eur
J Neurosci 12:405– 413.
Poletti CE, Cresswell G. 1977. Fornix system efferent projections in the
squirrel monkey: an experimental degeneration study. J Comp Neurol
175:101–128.
Rosene D, Roy NJ, Davis BJ. 1986. A cryoprotection method that facilitates
cutting frozen sections of whole monkey brains for histological and
histochemical processing without freezing artifact. J Histochem Cytochem 34:1301–1315.
Rosene DL, Van Hoesen GW. 1977. Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey.
Science 198:315–317.
Russchen FT, Bakst I, Amaral DG, Price JL. 1985. The amygdalostriatal
projections in the monkey. An anterograde tracing study. Brain Res
329:241–257.
Saleem KS, Hashikawa T. 1999. Immunohistochemical parcellation of the
inferotemporal cortex and medial temporal lobe structures in macaque
monkeys. Soc Neurosci Abstr 29:370.1.
Saleem KS, Tanaka K. 1996. Divergent projections from the anterior
inferotemporal area TE to the perirhinal and entorhinal cortices in
macaque monkey. J Neurosci 16:4757– 4775.
Saunders RC, Rosene DL. 1988. A comparison of the efferents of the
amygdala and the hippocampal formation in the rhesus monkey: I.
Convergence in the entorhinal, prorhinal, and perirhinal cortices.
J Comp Neurol 271:153–184.
Saunders RC, Rosene DL, Van Hoesen GW. 1988. A comparison of the
efferents of the amygdala and the hippocampal formation in the rhesus
monkey: II. Reciprocal and non-reciprocal connections. J Comp Neurol
271:185–207.
Schacter DL, Wagner AD. 1999. Medial temporal lobe activations in fMRI
and PET studies of episodic encoding and retrieval. Hippocampus
9:7–24.
Siegel A, Ohgami S, Edinger H. 1975. Projections of the hippocampus to
the septal area in the squirrel monkey. Brain Res 99:247–260.
Suzuki WA. 1996. The anatomy, physiology and functions of the perirhinal
cortex. Curr Opin Neurobiol 6:179 –186.
Turner BH, Gupta KC, Mishkin M. 1978. The locus and cytoarchitecture of
the projection areas of the olfactory bulb in Macaca mulatta. J Comp
Neurol 177:381–396.
Van Groen T, Wyss JM. 1990. Extrinsic projections from area CA1 of the
rat hippocampus: olfactory, cortical, subcortical, and bilateral hippocampal formation projections. J Comp Neurol 302:515–528.
Wright CI, Beijer AVJ, Groenewegen HJ. 1996. Basal amygdaloid complex
afferents to the rat nucleus accumbens are comparmentally organised.
J Neurosci 16:1877–1893.
Zaborszky L, Alheid GF, Beinfeld MC, Eiden LE, Heimer L, Palkovits M.
1985. Cholecystokinin innervation of the ventral striatum: a morphological and radioimmunological study. Neuroscience 14:427– 453.
Zahm DS, Heimer L. 1988. Ventral striatopallidal parts of the basal ganglia in the rat: I. Neurochemical compartmentation as reflected by the
distributions of neurotensin and substance P immunoreactivity.
J Comp Neurol 272:516 –535.