THE JOURNAL OF COMPARATIVE NEUROLOGY 508:212–237 (2008)
Projections of the Paraventricular and
Paratenial Nuclei of the Dorsal Midline
Thalamus in the Rat
ROBERT P. VERTES* AND WALTER B. HOOVER
Center for Complex Systems and Brain Sciences, Florida Atlantic University,
Boca Raton, Florida 33431
ABSTRACT
The paraventricular (PV) and paratenial (PT) nuclei are prominent cell groups of the
midline thalamus. To our knowledge, only a single early report has examined PV projections
and no previous study has comprehensively analyzed PT projections. By using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin, and the retrograde tracer,
FluoroGold, we examined the efferent projections of PV and PT. We showed that the output
of PV is virtually directed to a discrete set of limbic forebrain structures, including ‘limbic’
regions of the cortex. These include the infralimbic, prelimbic, dorsal agranular insular, and
entorhinal cortices, the ventral subiculum of the hippocampus, dorsal tenia tecta, claustrum,
lateral septum, dorsal striatum, nucleus accumbens (core and shell), olfactory tubercle, bed
nucleus of stria terminalis (BST), medial, central, cortical, and basal nuclei of amygdala, and
the suprachiasmatic, arcuate, and dorsomedial nuclei of the hypothalamus. The posterior PV
distributes more heavily than the anterior PV to the dorsal striatum and to the central and
basal nuclei of amygdala. PT projections significantly overlap with those of PV, with some
important differences. PT distributes less heavily than PV to BST and to the amygdala, but
much more densely to the medial prefrontal and entorhinal cortices and to the ventral
subiculum of hippocampus. As described herein, PV/PT receive a vast array of afferents from
the brainstem, hypothalamus, and limbic forebrain, related to arousal and attentive states of
the animal, and would appear to channel that information to structures of the limbic
forebrain in the selection of appropriate responses to changing environmental conditions.
Depending on the specific complement of emotionally associated information reaching PV/PT
at any one time, PV/PT would appear positioned, by actions on the limbic forebrain, to direct
behavior toward a particular outcome over a range of outcomes. J. Comp. Neurol. 508:
212–237, 2008. © 2008 Wiley-Liss, Inc.
Indexing terms: medial prefrontal cortex; subiculum of hippocampus; nucleus accumbens; bed
nucleus of stria terminalis; central and basal nuclei of amygdala
The paraventricular and paratenial nuclei are prominent cell groups of the midline thalamus (Swanson, 1998;
Van der Werf et al., 2002). The paraventricular nucleus
(PV) lies dorsally on the midline directly below the third
ventricle and extends rostrocaudally virtually throughout
the thalamus. The paratenial nucleus (PT) borders PV
laterally and overlaps with approximately the rostral onethird of PV.
Based on the early demonstration that low-frequency
stimulation of the midline and intralaminar nuclei of the
thalamus produced slow synchronous activity over widespread regions of the cortex (recruiting responses) (Dempsey and Morrison, 1942), the midline thalamus was
viewed as ‘nonspecific’ thalamus, exerting nonspecific or
© 2008 WILEY-LISS, INC.
global effects on the cortical mantle (Bentivoglio et al.,
1991; Groenewegen and Berendse, 1994). The notion, however, of the midline thalamus as ‘nonspecific’ has been
revised based on the subsequent anatomical demonstra-
Grant sponsor: National Institute of Mental Health; Grant numbers:
MH42900, MH63519.
*Correspondence to: Dr. Robert P. Vertes, Center for Complex Systems
and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431.
E-mail: Vertes@ccs.fau.edu
Received 29 August 2007; Revised 20 December 2007; Accepted 10 January 2008
DOI 10.1002/cne.21679
Published online in Wiley InterScience (www.interscience.wiley.com).
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
213
tion that nuclei of the midline thalamus do not project
widely throughout the neocortex, but rather selectively to
specific regions of cortex, primarily those of the prefrontal
cortex (Berendse and Groenewegen, 1991; Van der Werf et
al., 2002; Groenewegen and Witter, 2004; Vertes, 2006). In
addition, recent reports have shown that stimulation of
individual nuclei of the midline thalamus produce selective effects on their cortical targets—as opposed to widespread actions throughout the cortex (Dolleman-Van der
Weel et al., 1997; Bertram and Zhang, 1999; Kung and
Shyu, 2002; Zhang and Bertram, 2002; Viana Di Prisco
and Vertes, 2006).
In a series of reports, Groenewegen and colleagues (Berendse and Groenewegen, 1990, 1991; Berendse et al.,
1992; Groenewegen et al., 1999) showed that major targets of midline thalamic nuclei were the prefrontal cortex
and ventral striatum (nucleus accumbens, ACC), and further that recipient zones in the medial prefrontal cortex
(mPFC) and ACC were themselves directly connected
(mPFC to ACC). With respect to the paraventricular nucleus, PV distributes to the prelimbic cortex (of mPFC)
and to the medial shell region of ACC, and PL, in turn,
projects to the shell of ACC (Berendse and Groenewegen,
1990, 1991; Berendse et al., 1992).
Undoubtedly owing to the early emphasis on PV projections to the ventral striatum and to mPFC, subsequent
reports largely focused on these target sites. Using dual
retrograde labeling techniques, Otake and Nakamura
(1998) reported that of the nuclei of the midline thalamus,
PV contained the largest percentage of cells with collateral projections to ACC and mPFC. In like manner, Bubser and Deutch (1998) showed that ⬇15% of PV cells
distribute via collaterals to the medial shell of ACC and PL,
while Pinto et al. (2003) demonstrated that PV fibers terminate in close apposition to dopaminergic (DA) terminals in
nucleus accumbens, but not to DA terminals in the mPFC.
Abbreviations
AA
ac
AC
ACC,c,s
AGm
AGl
AH
AI,d,p,v
AM
AON
AV
BLA
BMA
BST
CA1,3
cc
CEA,c,l,m
CL
CLA
CM
COA,a,p
CP
DBh
DMh
EC,l
ECT
EN
fa
FG
FI
FP,l,m
FS
GI
GP
HF
IAM
IL
IMD
IP
LA
LD
LH
LHy
LO
LP
LPO
LS
MA
MD
MEA
Anterior amygdaloid area
Anterior commissure
Anterior cingulate cortex
Nucleus accumbens, core and shell divisions
Medial agranular (frontal) cortex
Lateral agranular (frontal) cortex
Anterior nucleus of hypothalamus
Agranular insular cortex, dorsal, posterior, ventral divisions
Anteromedial nucleus of thalamus
Anterior olfactory nucleus
Anteroventral nucleus of thalamus
Basolateral nucleus of amygdala
Basomedial nucleus of amygdala
Bed nucleus of stria terminalis
Field CA1 and CA3 of Ammon’s horn
Corpus callosum
Central nucleus of amygdala, capsular, lateral, and medial divisions
Central lateral nucleus of the thalamus
Claustrum
Central medial nucleus of thalamus
Cortical nucleus of amygdala, anterior, posterior divisions
Caudate-putamen
Nucleus of diagonal band, horizontal limb
Dorsomedial nucleus of hypothalamus
Entorhinal cortex, lateral division
Ectorhinal cortex
Endopiriform nucleus
Forceps of the corpus callosum
Fluorogold
Fimbria of hippocampus
Frontal polar cortex, lateral, medial divisions
Fundus of striatum
Granular insular cortex
Globus pallidus
Hippocampal formation
Interanteromedial nucleus of thalamus
Infralimbic cortex
Intermediodorsal nucleus of thalamus
Interpeduncular nucleus
Lateral nucleus of amygdala
Lateral dorsal nucleus of thalamus
Lateral habenula
Lateral hypothalamus
Lateral orbital cortex
Lateral posterior nucleus of thalamus
Lateral preoptic area
Lateral septum
Magnocellular preoptic nucleus
Mediodorsal nucleus of thalamus
Medial nucleus of the amygdala
MFB
MG
MH
MO
mPFC
MPO
MPN
MRF
MS
mt
OC
OT
PAp
PC
PFC
PH
PHA-L
PIR
PL
PO
PRC
PT
PV,a,p
RE
RH
RN
RSC
RT
SC
SCN
SI
sm
SM
SNr
SPZ
SSI
SSII
st
SUB,v
SUM
TE
TT,d,v
V3
VAL
VB
VL
VLO
VM
VO
VTA
ZI
Medial forebrain bundle
Medial geniculate nucleus of thalamus
Medial habenula
Medial orbital cortex
Medial prefrontal cortex
Medial preoptic area
Medial preoptic nucleus
Mesencephalic reticular formation
Medial septum
Mammillothalamic tract
Occipital cortex
Olfactory tubercle
Posterior parietal cortex
Paracentral nucleus of thalamus
Prefrontal cortex
Posterior nucleus of hypothalamus
Phaseolus vulgaris-leucoagglutinin
Piriform cortex
Prelimbic cortex
Posterior nucleus of thalamus
Perirhinal cortex
Paratenial nucleus of thalamus
Paraventricular nucleus of thalamus, anterior and posterior divisions
Nucleus reuniens of thalamus
Rhomboid nucleus of thalamus
Red nucleus
Retrosplenial cortex
Reticular nucleus of thalamus
Superior colliculus
Suprachiasmatic nucleus
Substantia innominata
Stria medullaris
Submedial nucleus of thalamus
Substantia nigra, pars reticulata
Subparaventricular zone of hypothalamus
Primary somatosensory cortex
Secondary somatosensory cortex
Stria terminalis
Subiculum, ventral division
Supramammillary nucleus
Temporal cortex
Tenia tecta, dorsal and ventral divisions
Third ventricle
Ventral anterior nucleus of thalamus
Ventral basal nucleus of thalamus
Lateral ventricle
Ventrolateral orbital cortex
Ventral medial nucleus of thalamus
Ventral orbital cortex
Ventral tegmental area
Zona incerta
The Journal of Comparative Neurology
214
To our knowledge, only a single report (Moga et al.,
1995) has examined the general distribution of PV projections “with special emphasis on the projections to the
hypothalamus and amygdala.” Focusing on circadian circuitry, Moga et al. (1995) described PV projections to the
suprachiasmatic nucleus (SCN) as well as to other sites
involved in circadian rhythms including the dorsomedial
nucleus and subparaventricular zone of the hypothalamus. These results, coupled with the demonstration that
PV receives input from all major components of the circadian system including SCN, led Moga et al. (1995) to
conclude that, “the anterior PV is ideally situated to relay
circadian timing information from the SCN to brain areas
involved in visceral and motivation aspects of behavior
and to provide feedback regulation of the SCN.” Consistent with this, Peng and Bentivoglio (2004) recently demonstrated at the light and electron microscopic (EM) levels
that SCN fibers synaptically contact PV cells projecting to
the amygdala and concluded that PV serves an important
role in the “transfer of circadian timing information to the
limbic system.”
PV receives a vast array of afferents from monoaminergic and neuropeptide containing systems of the brainstem
and hypothalamus—systems known to have activating
effects on the forebrain (Chen and Su, 1990; Vertes, 1991;
Freedman and Cassell, 1994; Bhatnagar et al., 2000;
Krout et al., 2002; Otake, 2005). Accordingly, PV (and
other midline thalamic nuclei) are thought to serve a
direct role in processes of arousal and attention (Krout et
al., 2002; Van der Werf et al., 2002; Vertes, 2002, 2006).
Consistent with a role for PV in attention, Kirouac et al.
(2005) recently showed that PV receives pronounced input
from orexin (hypocretin) containing cells as well as from
cocaine- and amphetamine-regulated transcript containing (CART) neurons of the hypothalamus (Kirouac et al.,
2006), and that both orexin and CART fibers synapse with
PV cells projecting to the shell of ACC (Parsons et al.,
2006). They proposed that PV links visceral/arousal systems to limbic forebrain regions involved in behavioral
responses (Parsons et al., 2006).
Taken as a whole, the foregoing suggests that PV may
represent an important relay in the transfer of visceral/
arousal, homeostatic, and circadian information to parts
of the limbic system—thereby priming them (state of
readiness) for behavioral responding. In this regard, PV
neurons show elevated levels of c-fos expression during
periods of wakefulness (compared to sleep) (Peng et al.,
1995) as well as during stressful conditions (Chastrette et
al., 1991; Bubser and Deutch, 1999; Sica et al., 2000;
Otake et al., 2002)—which could be seen as heightened
states of arousal. In view, then, of its pivotal role in limbic
circuitry, we sought to comprehensively examine the efferent projections of PV in the rat.
Although the paratenial nucleus of the thalamus also
appears to receive a vast array of afferent information
(Chen and Su, 1990; Krout et al., 2002) and may selectively target structures of the limbic forebrain (Kelley and
Stinus, 1984; Carlsen and Heimer, 1986), little is known
regarding the connections of PT. The purpose, then, of the
present study was to analyze, compare, and contrast efferent projections of PV and PT nuclei of the midline
thalamus. We show that, with some important differences,
the output of both PV and PT is mainly directed to the
medial prefrontal and entorhinal cortices, the ventral subiculum of the hippocampus, claustrum, the dorsal and
R.P. VERTES AND W.B. HOOVER
ventral striatum, lateral septum, bed nucleus of stria terminalis, and to most of the amygdala, with a concentration in the central and basal nuclei of the amygdala.
Materials and Methods
Single injections of Phaseolus vulgaris-leucoagglutinin
(PHA-L) were made into either the PV or PT nuclei of the
midline thalamus in 31 male Sprague–Dawley rats
(Charles River, Wilmington, MA) weighing 275– 400 g. Of
the 31 injections, 10 were confined to PV, 8 were confined
to PT, 4 overlapped PV and PT, 4 overlapped PV and the
mediodorsal nucleus (MD); 3 overlapped PV and the intermediodorsal nucleus (IMD), and 2 were localized to the
interanteromedial nucleus (IAM). Another 16 male
Sprague–Dawley rats weighing 350 – 450 g received single
injections of the retrograde fluorescent tracer FluoroGold
(FG) (Fluorochrome, Denver, CO) into some PV and PT
targets: the central (CEA) and basolateral (BLA) nuclei of
the amygdala and the core and shell of nucleus accumbens. Of the 16 injections, seven were made in CEA or
BLA of the amygdala and three were control injections in
other nuclei of the amygdala. Of the seven injections in the
central and basal nuclei of the amygdala, two were made
in CEA, two in the basolateral nucleus (BLA), two in BLA
and CEA, and one in BLA and the basomedial nucleus. Of
the six injections in nucleus accumbens, three were localized to the core of ACC and three to the shell of ACC. The
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.
PHA-L procedures
Powdered lectin from PHA-L was reconstituted to 4 –5%
in 0.05 M sodium phosphate buffer (PB), pH 7.4. The
PHA-L solution was iontophoretically deposited in the
brains of anesthetized rats (sodium pentobarbital, 75 mg/
kg, ip) by means of a glass micropipette with an outside tip
diameter of 40 – 60 ␮m. Positive direct current (5–10 ␮A)
was applied through a Grass stimulator (Model 88) coupled with a high voltage stimulator (Frederick Haer, Bowdoinham, ME) at 2 seconds “on” / 2 seconds “off” intervals
for 40 –50 minutes. After a survival time of 7–10 days, rats
were deeply anesthetized with sodium pentobarbital and
perfused transcardially with a heparinized buffered saline
wash (100 mL/animal) followed by a fixative (4% paraformaldehyde, 0.2– 0.5% glutaraldehyde in 0.1 M phosphate
buffer, pH 7.4) (300 –500 mL/animal). The brains were
removed and stored for 2 days at 4°C in 30% sucrose in 0.1
M PB. On the following day, 50-␮m frozen sections were
collected in phosphate-buffered saline (PBS, 0.9% sodium
chloride in 0.01 M sodium phosphate buffer, pH 7.4) using
a sliding microtome. Six series of sections were taken. A
complete series of sections was treated with 1% sodium
borohydride in 0.1 M PB for 30 minutes to remove excess
reactive aldehydes. Sections were then rinsed in 0.1 M PB,
followed by 0.1 M Tris-buffered saline (TBS), pH 7.6. Following this, sections were incubated for 60 minutes at
room temperature (RT) in 0.5% bovine serum albumin
(BSA) in TBS to minimize nonspecific labeling. The sections were then incubated overnight at RT in diluent
(0.1% BSA in TBS containing 0.25% Triton X-100) and
biotinylated goat anti PHA-L (Vector Labs, Burlingame,
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
CA) at a concentration 1:500. Sections were then washed
in 0.1 M PB (4 ⫻ 8 minutes) and placed in a 1:500 concentration of biotinylated rabbit antigoat immunoglobulin
(IgG) and diluent for 2 hours. Sections were washed and
then incubated in a 1:100 concentration of peroxidaseavidin complex from the Elite kit (Vector) and diluent for
1 hour. Following another 0.1 M PB wash the peroxidase
reaction product was visualized by incubation in a solution containing 0.022% 3,3⬘ diaminobenzidine (DAB, Aldrich, Milwaukee, WI) and 0.003% H2O2 in TBS for 6
minutes. Sections were then rinsed again in PBS (3 ⫻ 1
minutes) and mounted onto chrome-alum gelatin-coated
slides. An adjacent series of sections from each rat was
stained with cresyl violet for anatomical reference. Sections were examined using light and darkfield optics. Injection sites, cells, and labeled fibers were plotted on representative schematic coronal sections through the brain
using sections adapted from the rat atlas of Swanson
(1998). Brightfield and darkfield photomicrographs of injection sites and labeled fibers were taken with a Nikon
DXM1200 camera mounted on a Nikon Eclipse E600 microscope. Digital images were captured and reconstructed
using Image-Pro Plus 4.5 (Media Cybernetics, Silver
Springs, MD), and adjusted for brightness and contrast
using Adobe PhotoShop 7.0 (Mountain View, CA). Patterns of labeling were classified as light, moderate, and
dense (Table 1), with ‘light’ referring to a few labeled
fibers widely dispersed throughout a structure, ‘dense’ as
a heavy concentration of labeled fibers generally occupying a significant portion (or most) of a structure, and
‘moderate’ between these two patterns.
FluoroGold procedures
FluoroGold (FG) (Fluorochrome) was dissolved in a 0.1
M sodium acetate buffer (pH 4.0 to 5) to yield a 4 –5%
concentration. The FG solution was iontophoretically deposited in the brains of anesthetized rats by means of a
glass micropipette with an outside tip diameter of 25–50
␮m. Single FG injections were made into one of four structures in separate rats: the central and basolateral nuclei
of the amygdala and the core and shell of ACC. The procedures for FG injections were basically the same as described for PHA-L injections, with the following exceptions: 1) the outside tip diameter of the glass
micropipettes was 25–50 ␮m, and 2) the length of injections was 2–10 minutes. 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 PB, pH 7.4). The
brains were then removed and stored for 48 hours in a
sucrose solution (30% sucrose in 0.1 M PB) at 4°C. Following this, 50-␮m coronal sections were taken on a freezing
microtome and collected in 0.1 M PB and stored at 4°C. Six
series of sections were taken. A complete series of sections
was incubated in a sodium borohydride solution (1% sodium borohydride in 0.1 M PB) for 30 minutes, and
washed with 0.1M PB four times at 6 minutes each (4 ⫻ 6
min). The sections were then blocked in a Tris-saline
solution (0.5% BSA, Sigma Chemicals, St. Louis, MO;
0.25% Triton X-100 in 0.1 M Tris-saline, pH 7.6) for 1
hour. Following the blocking procedure the sections were
incubated for 48 hours at RT in a primary antiserum
directed against FG (rabbit anti-FluoroGold) (Chemicon,
Temecula, CA) at a concentration of 1:1,000 in diluent.
215
TABLE 1. Relative Density of Anterogradely Labeled Fibers Produced by
PHA-L Injections into PVa, PVp, and PT of the Midline Thalamus
Labeling
Structure
Telencephalon
Cortex
Agranular insular, dorsal
Agranular insular, posterior
Agranular insular, ventral
Agranular, lateral (primary motor)
Agranular, medial (secondary motor)
Anterior cingulate, dorsal
Anterior cingulate, ventral
Ectorhinal
Entorhinal
Frontal polar, lateral
Frontal polar, medial
Granular insular
Infralimbic
Lateral orbital
Medial orbital
Parietal
Perirhinal
Piriform
Prelimbic
Retrosplenial
Subiculum, ventral
Somatosensory, secondary
Ventral Orbital
Ventrolateral Orbital
Accumbens n.
Core
Shell
Amygdala
Anterior amygdaloid area
Basolateral n.
Basomedial n.
Central n.
Cortical n.
Lateral n.
Medial n.
Posterior n.
Amygdaloid-piriform area
Bed n. of stria terminalis
Claustrum
Diagonal band of Broca, horizontal
Endopiriform n.
Globus pallidus
Medial preoptic area
Olfactory tubrical
Septum
Medial
Lateral
Striatum
Substantia innominata
Tenia tecta
Diencephalon
Hypothalamus
Arcuate n.
Dorsomedial n.
Lateral hypothalamic area
Paraventricular n.
Posterior hypothalamus
Suprachiasmatic n.
Supramammillary n.
Thalamus
Central medial n.
Interanteromedial n.
Mediodorsal n.
Parafascicular n.
Parataenial n.
Paraventricular n.
Reticular n.
Reuniens n.
Rhomboid n.
PVa
PVp
PT
⫹⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫹
⫺
⫹
⫹
⫹⫹
⫺
⫹⫹
⫺
⫹⫹
⫺
⫹⫹
⫹⫹
⫺
⫺
⫺
⫹
⫹
⫹⫹
⫹⫹
⫹
⫹
⫹⫹
⫹⫹⫹
⫺
⫹
⫺
⫹⫹
⫹⫹⫹
⫺
⫹⫹
⫺
⫺
⫺
⫹⫹⫹
⫹
⫺
⫺
⫺
⫹⫹⫹
⫹⫹
⫹
⫹⫹⫹
⫺
⫹⫹⫹
⫺
⫹⫹⫹
⫺
⫹⫹⫹
⫺
⫹⫹
⫹⫹
⫹⫹⫹
⫹
⫹⫹
⫺
⫹⫹
⫺
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹
⫹
⫹⫹
⫹⫹⫹
⫺
⫺
⫺
⫺
⫺
⫹⫹⫹
⫹⫹
⫺
⫺
⫹
⫺
⫹⫹
⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫺
⫺
⫹⫹⫹
⫹⫹
⫺
⫺
⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹
⫺
⫺
⫺
⫹
⫹⫹⫹
⫺
⫹
⫹⫹
⫺
⫹
⫺
⫹⫹
⫹⫹⫹
⫹
⫹⫹
⫺
⫹⫹⫹
⫹⫹⫹
⫺
⫹⫹
⫹⫹
⫹
⫺
⫺
⫺
⫹⫹
⫺
⫺
⫹⫹
⫺
⫺
⫺
⫹⫹
⫺
⫺
⫺
⫹⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫹, light labeling; ⫹⫹, moderate labeling; ⫹⫹⫹, dense labeling; ⫺, absence of labeling;
n, nucleus
Following incubation in the primary antiserum, sections
were washed (4 ⫻ 6 min) in 0.1 M PB, then incubated in a
secondary antiserum (biotinylated goat antirabbit IgG)
(Vector) at a concentration of 1:500 in diluent for 2 hours.
Sections were then washed again (4 ⫻ 6 minutes) and
The Journal of Comparative Neurology
216
Fig. 1. High-power brightfield photomicrographs at two levels of
magnification of PHA-L injections sites in the anterior paraventricular nucleus (A,B), the posterior paraventricular nucleus (C,D), and
the paratenial nucleus (E,F) of the dorsal midline thalamus. Note
R.P. VERTES AND W.B. HOOVER
clearly visible PHA-L filled cells in PVa (B), PVp (D), and PT (F). Scale
bar ⫽ 375 ␮m for A,E; 200 ␮m for B; 400 ␮m for C; 300 ␮m for D; 225
␮m for F.
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
217
Fig. 2. Schematic representation of labeling present in select sections through the forebrain and
midbrain (A–N) produced by a PHA-L injection (dots in I,J) in the anterior part of the paraventricular
nucleus of the thalamus (case 6). Sections modified from the rat atlas of Swanson (1998). See list for
abbreviations.
incubated in avidin-biotin complex (Vector) at a 1:100
concentration in diluent for 1 hour. After a final set of 4 ⫻
6 minute rinses the peroxidase reaction product was visualized by incubation in a solution containing 0.022% of
DAB (Aldrich), 0.015% nickel chloride (NiCl), and 0.003%
H2O2 in TBS for 6 minutes. Sections were rinsed again in
PBS (3 ⫻ 1 minutes) and mounted onto chrome-alum
gelatin-coated slides. An adjacent series of representative
sections from each rat was stained with cresyl violet for
anatomical reference. The resulting material was pro-
The Journal of Comparative Neurology
218
R.P. VERTES AND W.B. HOOVER
Figure 2
cessed for presentation as described for the PHA-L sections.
Results
The pattern of distribution of projections from the PV
and PT nuclei of the thalamus are described. Figure 1
shows sites of injection in the anterior PV (PVa) (Fig.
1A,B), the posterior PV (PVp) (Fig. 1C,D), and PT (Fig.
1E,F) at two levels of magnification. As depicted, PHA-Lfilled cells are restricted to respective nuclei. The patterns
of labeling obtained with the schematically depicted cases
are representative of patterns seen with nonillustrated
cases.
(Continued)
Anterior paraventricular nucleus (PVa)
(case 6)
Figure 2 schematically depicts the pattern of distribution of labeled fibers following a PHA-L injection in the
anterior part of PV (case 6). As shown, labeled fibers
coursed ventrolaterally from the site of injection (Fig. 2F)
within the thalamic peduncle to regions of the lateral
hypothalamus and from there took three principal routes.
A major contingent continued ventrolaterally in amygdalopetal pathways to reach the amygdala and surrounding regions of cortex, others coursed rostrally to the anterior forebrain primarily bound for the ventral striatum
and the prefrontal cortex or caudally en route to regions of
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EFFERENTS OF PV AND PT NUCLEI
the hypothalamus. Some labeled fibers of the ascending
bundle joined the stria terminalis and traveled with it to
reach the amygdala and adjacent regions of cortex.
Overall, labeling was light at the anterior pole of the
forebrain (Fig. 2A,B). A small collection of labeled fibers
was seen along the medial wall of the prefrontal cortex
(PFC), mainly within the anterior prelimbic (PL) cortex.
Some diffuse labeling was also observed in the dorsal
tenia tecta (TTd) (Fig. 2A,B).
Further caudally at the rostral forebrain (Fig. 2C,D),
labeling was primarily confined to PL of the mPFC and to
rostral aspects of nucleus accumbens (ACC). As depicted
in Figure 3A, labeled fibers mainly encircled the outer
boundaries of ACC, and were much less concentrated in
the core of the rostral ACC. Additional labeled sites were
the anterior claustrum (CLA), ventromedial regions of the
dorsal striatum bordering ACC (Fig. 2D), and to a lesser
degree the dorsal agranular insular cortex (AId) (Fig. 2C).
There was a noticeable lack of labeling at this level (Fig.
2C), as well as caudally, over most of the cortical mantle.
Labeling was stronger on the left than on the right side of
the brain (Fig. 2A–M), reflecting the fact that the PV
injection was slightly lateralized to the left side (Fig.
1A,B).
At septal levels (Fig. 2D–H), labeling was pronounced
and relatively restricted to the core and shell regions of
ACC, to ventral aspects of the lateral septum (LS) (Figs.
2F, 3B), and to the bed nucleus of the stria terminalis
(BST). The dense labeling within the shell of ACC and to
a slightly lesser degree in the core of ACC is depicted in
the photomicrographs of Figure 3B, while equally pronounced labeling of BST, above and below the anterior
commissure, is shown in Figure 3C. Outside of these sites,
CLA, the olfactory tubercle (OT), and ventral regions of
the dorsal striatum were moderately labeled, while the
ventral globus pallidus (Fig. 2H) was lightly labeled.
At mid levels of the forebrain (Fig. 2I–K), labeling was
mainly confined to the amygdala and parts of the hypothalamus. The arcuate and suprachiasmatic (SCN) (Fig.
2I) nuclei of the hypothalamus were moderately labeled.
Within the (rostral) amygdala, labeling was very heavy
within the central nucleus (CEA) (Fig. 2J,K), particularly
within the lateral CEA (Fig. 3D), moderately dense in the
basomedial (BMA) and basolateral (BLA) nuclei, and relatively light in the medial and cortical nuclei of amygdala.
Some labeled fibers were also present on the lateral convexity of cortex within the posterior agranular insular
cortex, rostrally (Fig. 2I,J) and in the perirhinal (PRC),
rostral entorhinal (EC) and piriform cortices, caudally
(Fig. 2K).
At further caudal levels of the forebrain (Fig. 2L,M) and
the rostral midbrain (Fig. 2N), the bulk of labeled fibers
was localized to the amygdala and surrounding regions
including caudal parts of the dorsal striatum (Fig. 2L,M),
deep layers of the perirhinal, entorhinal and piriform cortices (Fig. 2L–N), and the ventral subiculum of the hippocampus (Fig. 2N). Within the amygdala, labeling was
predominantly restricted to the basal nuclei— dense
within BMA and moderate within the medial part of BLA.
Some labeled fibers were also present in the posterior PV
(PVp) and in the dorsomedial nucleus of the hypothalamus (Fig. 2L,M).
219
Posterior paraventricular nucleus (PVp)
(case 32)
Anterior and posterior PV injections largely gave rise to
similar patterns of labeling but, as described below, overall density of labeling was stronger with PVp than with
PVa injections.
Labeled fibers from PVp mainly coursed rostrally
through the dorsal thalamus (Fig. 4K–N) and approximately at the level of the rostral pole of the hippocampus
(Fig. 4I,J) turned ventrolaterally to exit the thalamus.
From there, they either continued on the same trajectory
to reach the amygdala and surrounding regions of the
dorsal striatum and cortex or ascended or descended
through the medial forebrain bundle (MFB) en route to
the basal forebrain and prefrontal cortices, rostrally, or to
parts of the hypothalamus, caudally.
Similar to PVa, labeling at the anterior pole of the
forebrain (Fig. 4A,B) was generally moderate and mainly
present in inner layers of the anterior PL and anterior
cingulate (AC) cortices and to considerably lesser degrees
in medial frontal polar (FPm), medial orbital (MO), and
dorsal agranular insular (AId) cortices. Moderate numbers of labeled axons were also visible in TTd.
Further caudally at the rostral forebrain (Fig. 4C), labeled fibers spread widely over ventral aspects of the brain
mainly localized to the ventral mPFC, claustrum, dorsal
agranular insular cortex (AId), rostral ACC, and the olfactory tubercle (OT). As depicted (Fig. 4C), labeling was
quite dense in the inner layers of the infralimbic (IL) and
prelimbic cortices and somewhat less pronounced in AId,
CLA, rostral ACC, and OT. A few labeled fibers were also
seen in AC.
The main targets of labeled fibers further caudally in
the forebrain were the dorsal and ventral striatum (Fig.
4D–F). As depicted schematically (Fig. 4D,E) and in the
micrograph of Figure 5A, the shell of ACC (ACCs) was
intensely labeled. With the exception of the region surrounding the anterior commissure, which was heavily labeled, the core of ACC (ACCc) was moderately labeled.
Unlike PVa, significant numbers of labeled axons were
also present in ventral aspects of the dorsal striatum (CP),
progressively thinning from the ventrolateral to dorsomedial CP. Other moderately to heavily labeled sites at these
levels were ventral LS, OT, CLA, and AId (Fig. 4D–F).
Immediately caudal to ACC (Fig. 4F–H), labeled axons
spread densely throughout the extent of the bed nucleus of
the stria terminalis (BST) and were also present in sizeable numbers in medial aspects of CP, CLA, OT, AId, and
the suprachiasmatic nucleus (SCN). Figure 5B shows a
discrete group of labeled axons bilaterally within SCN.
Additional light to moderately labeled sites included the
posterior agranular insular cortex (AIp) (with some extension dorsally into the granular insular cortex), substantia
innominata (SI), medial preoptic area (MPO) and the globus pallidus (GP) (Fig. 4F–H).
At mid to caudal levels of the forebrain (Fig. 4I–N),
labeled fibers were mainly confined to the dorsal striatum and to the amygdala, spreading massively throughout the amygdala. As shown (Figs. 4I–N, 6A–D), labeled
fibers virtually blanketed the amygdala, with the densest concentration in the central (CEA) (Fig. 6A,B) and
basomedial (BMA) (Fig. 6A–D) nuclei of amygdala. The
medial (MEA) and basolateral nuclei of amygdala were
also fairly heavily labeled, whereas the lateral and
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220
R.P. VERTES AND W.B. HOOVER
Fig. 3. A–D: Low-magnification darkfield photomicrographs of
transverse sections through anterior (A–C) and posterior (D) regions
of the forebrain depicting patterns of labeling in rostral and caudal
nucleus accumbens (ACC) (A,B), the bed nucleus of the stria terminalis (C), and the amygdala (D) produced by a PHA-L injection into
anterior paraventricular nucleus of thalamus. A: Note that labeled
fibers mainly encircle but largely avoid the central core of the rostral
ACC, and also note significant labeling in the prelimbic cortex (PL) of
the medial prefrontal cortex. B: By contrast with the rostral ACC (A),
labeled fibers distribute massively to caudal part of ACC. Note pronounced labeling in both the shell and core of ACC, with additional
labeling in the adjacent lateral septum (LS) and ventromedial parts of
the dorsal striatum (caudate-putamen) (CP). C: Note strong terminal
labeling in BST above and below the anterior commissure. D: Note a
dense aggregate of labeled fibers in the central medial and medial
part of the medial part of the basomedial nucleus and prominent but
less dense labeling in the basolateral nucleus of the amygdala. Scale
bar ⫽ 550 ␮m for A; 500 ␮m for B–D. See list for abbreviations.
parts of the anterior and posterior cortical nuclei of
amygdala were moderately labeled (Fig. 4I–N). At pre
and beginning levels of the hippocampus (Fig. 4H–K), a
relatively narrow band of labeled fibers within the me-
dial CP, abutting the globus pallidus, was observed.
Labeling was densest ventrally in medial CP (Fig.
4I–M) at its point of merger with medial aspects of the
amygdala.
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EFFERENTS OF PV AND PT NUCLEI
221
Fig. 4. Schematic representation of labeling present in select sections through the forebrain and
midbrain (A–O) produced by a PHA-L injection (dots in N) in the posterior part of the paraventricular
nucleus of the thalamus (case 32). Sections modified from the rat atlas of Swanson (1998). See list for
abbreviations.
Further caudally (Fig. 4L–N), labeled fibers were found
to extend laterally from the medial CP to occupy most of
the mediolateral expanse of the caudal CP. In addition, as
rostrally, posterior parts of the lateral, central, basal
(BMA and BLA), and cortical nuclei of amygdala were
moderately to densely labeled (Fig. 4L–N). Significant
numbers of labeled axons were also visible within inner
layers of the parahippocampal and piriform cortices; that
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222
R.P. VERTES AND W.B. HOOVER
Figure 4
(Continued)
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EFFERENTS OF PV AND PT NUCLEI
is, a continuous column in layers 5 and 6 stretching from
the ectorhinal, perirhinal, and entorhinal cortices to the
piriform cortex (Fig. 4L–N). Although most regions of the
diencephalon were devoid of labeled fibers (Fig. 4L–N),
223
moderate numbers were present in the dorsomedial nucleus of the hypothalamus (DMH) (Fig. 5C) and a few
within the midline thalamus–reuniens (RE) and rhomboid
(RH) nuclei.
At the level of the midbrain (Fig. 4O) moderate numbers
of labeled fibers were present in the caudal perirhinal
cortex, lateral EC, and the ventral subiculum of the ventral hippocampus. Although labeling progressively
thinned caudally, labeled axons continued to be present in
lateral EC and the ventral subiculum throughout caudal
reaches of the brain (not shown). With a few exceptions,
there was a general absence of labeling at the rostral
midbrain (Fig. 4O) and throughout the brainstem.
Paratenial nucleus (PT) (case 27)
As depicted (Fig 1E,F), the injection in the paratenial
nucleus (PT) was confined to left PT, and accordingly
labeling was virtually restricted to the left side of the
brain. Labeling was minimal contralateral to the injection. Similar to PV, labeled fibers from PT exited ventrolaterally through the thalamus and then either continued
on the same course to the amygdala or ascended through
the MFB to the anterior forebrain or descended in the
MFB to parts of the caudal diencephalon.
At anterior pole of the forebrain (Fig. 7A,B), virtually
the entire medial wall of the mPFC was densely labeled.
This includes the medial frontal polar, prelimbic (PL), and
medial orbital (MO) cortices, rostrally (Fig. 7A) and the
anterior cingulate, PL, and MO cortices, further caudally
(Fig. 7B). This is shown in the photomicrographs of Figure
8A,B. As depicted, labeled fibers spread to all layers of
respective cortices, but were most heavily concentrated in
layers 2/3 of PL and the ventrally adjacent MO. In addition, moderate numbers of labeled fibers were present in
the ventral orbital cortex (VO) and TTd, but considerably
fewer in AId.
Further caudally in the anterior forebrain (Fig. 7C),
labeling remained pronounced along the medial wall of
the ventral mPFC, particularly pronounced in layers 1/3 of
the infralimbic (IL) and prelimbic cortices (Figs. 7C, 8C,
9). Equally dense labeling was observed within the rostral
ACC and parts of OT. Additional lightly to moderately
labeled sites included AId, AC, and the CLA. This pattern
of labeling is depicted in the brightfield photomicrograph
of Figure 9.
At early septal levels (Fig. 7D–F), labeled axons were
primarily localized to the ventral mPFC, CP, ventral striatum, CLA, and AId. Labeling was pronounced (or massive) in IL and PL of the mPFC, ventromedial sectors of
CP, the core and shell of ACC, and parts of OT (Fig. 7D–F).
Some regions of AC, AId, and LS were also heavily labeled
(Fig. 7E,F). As depicted schematically (Fig. 7D–F) and in
Fig. 5. A–C: Low-magnification darkfield photomicrographs of
transverse sections through the forebrain depicting patterns of labeling produced by a PHA-L injection into posterior paraventricular
nucleus. A: Note the massive labeling throughout the shell division of
the nucleus accumbens (ACCs) and intense but lesser labeling in the
core of ACC (ACCc) surrounding the anterior commissure. B: Note the
strong labeling bilaterally in the suprachiasmatic nucleus of the hypothalamus (SCN) above the optic chiasm. C: Note the pronounced
labeling bilaterally in the dorsomedial nucleus (DMh) of the hypothalamus lateral to the third ventricle. Scale bar ⫽ 500 ␮m for A; 250 ␮m
for B; 300 ␮m for C. See list for abbreviations.
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224
R.P. VERTES AND W.B. HOOVER
Fig. 6. A–D: Series of low-magnification darkfield photomicrographs of transverse sections rostrocaudally through the forebrain
(A–D) depicting patterns of labeling within the amygdala produced by
a PHA-L injection into posterior paraventricular nucleus. A,B: Note
very intense dense labeling in the central (CEA), basomedial (BMA)
and basolateral nuclei of amygdala, and prominent but less dense
labeling in the parts of the medial (MEA), lateral (LA), and anterior
cortical nuclei of amygdala. C,D: Note labeling at caudal levels of the
amygdala mainly confined to BMA and BLA. Scale bar ⫽ 750 ␮m. See
list for abbreviations.
the photomicrograph of Figure 10A, labeling was uneven
mediolaterally across ACC and within bordering regions
of CP; that is, dense in the internal (medial) shell of ACC,
considerably lighter in the lateral shell (with some relatively clear pockets), very strong in the (dorsal) core of
ACC, extending into the ventromedial CP, and moderate
in the lateral CP.
At caudal levels of the septum (Fig. 7G,H) significant
numbers of labeled axons were present in rostral BST, on
the lateral and ventral border of the anterior commissure,
and medially within CP abutting lateral wall of the lateral
ventricle, dorsal to BST. Light to moderate labeling was
also observed in AC, LS, ventromedial CP, olfactory tubercle, and CLA.
There was marked decline in labeling further caudally
in the forebrain (Fig. 7I–K) with labeled fibers mainly
observed in the rostral amygdala and adjoining regions of
the piriform cortex. As shown (Fig. 7I–K), labeled fibers
spread widely (and moderately) throughout the amygdala
to the anterior amygdaloid area (AA), CEA, MEA, BLA,
BMA, and the anterior cortical nucleus (COAa). There was
a noticeable absence of labeling in the core of CEA (Fig
7J,K). Other lightly to moderately labeled sites were AC,
dorsomedial CP, CLA, and anterior and lateral nuclei of
the hypothalamus.
At mid-levels of the forebrain (Fig. 7L–N), labeled
fibers were essentially confined to the ventrolateral sector of the brain; that is, to CP, to the amygdala, and to
the perirhinal, entorhinal, and piriform cortices. An
intensely labeled band of tissue stretching diagonally
through the amygdala was observed (Fig. 7L–N, 10B)
that included medial aspects of the lateral and basolat-
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EFFERENTS OF PV AND PT NUCLEI
225
Fig. 7. Schematic representation of labeling present in select sections through the forebrain and
midbrain (A–O) produced by a PHA-L injection (dots in I,J) in the paratenial nucleus of the thalamus
(case 27). Sections modified from the rat atlas of Swanson (1998). See list for abbreviations.
eral amygdala and virtually the extent of posterior
BMA. As rostrally, the core of CEA was largely devoid of
labeled fibers (Fig. 7L), but moderate numbers were
seen in the capsular CEA as well as in the posterior,
amygdaloid-piriform area, and posterior cortical nuclei
of the amygdala (Fig. 7L–N). A few labeled fibers were
also present in RE, the zona incerta (ZI), and throughout the lateral hypothalamus.
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226
R.P. VERTES AND W.B. HOOVER
Figure 7
(Continued)
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EFFERENTS OF PV AND PT NUCLEI
227
Fig. 8. A–C: Series of rostrocaudally (A–C) aligned lowmagnification darkfield photomicrographs of transverse sections
through the anterior forebrain depicting patterns of labeling within
the medial prefrontal cortex (mPFC) produced by a PHA-L injection
into the paratenial nucleus of the thalamus. Note the presence of
intense labeling along the ventral medial wall of the mPFC mainly
confined to the prelimbic (PL) (A–C), medial orbital (MO) (A,B), and
infralimbic (C) (IL) cortices. As depicted, labeling was particularly
dense in layers 1 and 3 of these prefrontal fields. Scale bar ⫽ 750 ␮m.
At the rostral midbrain (Fig. 7O), labeled fibers continued to mainly occupy ventrolateral regions of the
brain localized to perirhinal cortex, lateral EC, and the
ventral subiculum of the hippocampus. This pattern of
labeling is depicted in the micrographs of Figure 11A–C
showing prominent labeling in these areas—
particularly dense rostrocaudally throughout the lateral EC. The few labeled fibers present dorsally in the
retrosplenial cortex (Fig. 7O) mainly appeared bound
for the dorsal subiculum which was lightly labeled
(Fig. 7O).
ACCs injections; and 3) labeling was slightly stronger in
PVp with ACCc than ACCs injections. This supports anterograde results showing pronounced terminal labeling
in the shell and core of ACC with PVa, PVp, and PT
injections.
Figure 13 shows FG injections in the rostral BLA (Fig.
13A) and rostral CEA (Fig. 13D), together with patterns
of cell labeling in PVa and PT (Fig. 13B,E) and PVp (Fig.
13C,F) produced by these injections. As depicted, there
is a small number of labeled neurons in PT (Fig. 13B)
with the BLA injection and fewer still in PT (Fig. 13E)
with the CEA injection. This is consistent with anterograde findings showing light terminal labeling in rostral
BLA (Fig. 7I,J) and general lack of labeling in rostral
CEA (Fig. 7I,J) with PT injections. FG injections in BLA
gave rise to pronounced cell labeling in PVp (Fig. 13C), but
light labeling in PVa (Fig. 13B), while those in CEA produced significant labeling in both PVa (Fig. 13E) and PVp
(Fig. 13F). This is consistent with anterograde results demonstrating strong terminal labeling in rostral CEA with PVa
(Fig. 2I,J) and with PVp injections (Figs. 4I,J, 6A,B), as well
as weak labeling in BLA with PVa injections (Fig. 2I,J) and
dense labeling in BLA (Figs. 4I,J, 6A) with PVp injections.
As depicted, labeled cells are also present in RE (Fig. 13B,E),
the intermediodorsal (IMD), and the central medial (CM)
nuclei of the thalamus (Fig. 13C,F) with BLA and CEA
injections.
Retrograde tracing experiments
Two major destinations of labeled fibers of PVa, PVp,
and PT were the nucleus accumbens (shell and core) and
the amygdala—mainly CEA and basal nuclei (see above).
To confirm anterograde findings and provide further information on the distribution of PV and PT fibers to these
sites, retrograde injections (FG) were made in ACC and
the amygdala and patterns of labeling in PV and PT
determined.
Figure 12 shows FG injections in the shell (Fig. 12A)
and the core (Fig. 12D) of ACC together with patterns of
cell labeling in PVa and PT (Fig. 12B,E) and PVp (Fig.
12C,F) obtained with these injections. As depicted: 1) labeled cells were present in PVa, PVp, and densely in PT
with injections in the shell (ACCs) and core (ACCc) of
ACC; 2) labeling was heavier in PVa with ACCc than
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228
R.P. VERTES AND W.B. HOOVER
(LS), the core and shell of ACC, OT, BST, several nuclei of
the amygdala, including the lateral, medial, central, basal
(BLA and BMA), and the anterior and posterior cortical
nuclei, and the suprachiasmatic (SCN), arcuate, and dorsomedial nuclei of the hypothalamus. Secondary targets
were the anterior cingulate and ectorhinal cortices, dorsal
tenia tecta (TTd), the medial preoptic area, reuniens (RE),
and rhomboid nuclei of the thalamus and the lateral hypothalamus.
There is a significant overlap in projections from the
anterior (PVa) and posterior (PVp) PV (Figs. 2, 4; Table 1).
With some exceptions, PVp is the source of stronger projections to most commonly innervated sites. Perhaps the
most significant difference between PVa and PVp projections is that PVa distributes minimally to the dorsal striatum (caudate-putamen), whereas PVp projects quite
massively to CP, mainly to medial/ventromedial regions of
CP. In addition, while PVa and PVp project commonly to
the amygdala, PVp distributes more widely and heavily
throughout the amygdala than PVa, particularly to the
basal nuclei of amygdala. On the other hand, PVa is the
source stronger projections to the ventral subiculum of the
hippocampus.
Overview of PT projections and
comparisons with PV projections
Fig. 9. Low-magnification brightfield photomicrograph of a transverse section through the anterior forebrain depicting patterns of
labeling within the anterior cingulate (AC), prelimbic (PL), infralimbic (IL), and dorsal agranular insular cortices, the olfactory tubercle
(OT), and the rostral pole of the nucleus accumbens (ACC) produced
by a PHA-L injection in the paratenial nucleus of thalamus. Scale
bar ⫽ 500 ␮m. See list for abbreviations.
Discussion
We examined, compared, and contrasted the efferent
projections of the PV and PT nuclei of the dorsal midline
thalamus in the rat. The main (or virtually sole) targets of
PV and PT were ‘limbic/limbic related’ structures of the
forebrain. With the possible exception of the piriform cortex, there was essentially lack of PV/PT projections to
‘nonlimbic’ regions of the cortex including sensorimotor,
special sensory, or associational cortices as well as few
projections to most of the thalamus and hypothalamus. As
developed below, based on widespread afferents from the
brainstem and hypothalamus coupled with output to select structures of the limbic forebrain, PV/PT appear critical for routing visceral/emotional information to structures of the limbic forebrain, including the limbic cortex,
in the control of goal-directed behaviors.
Overview of PV projections and comparisons
between PVa and PVp projections
The main targets of PV (anterior and posterior parts)
were the prelimbic (PL), dorsal agranular insular, perirhinal (PRC) and entorhinal cortices, the ventral subiculum
of the hippocampus, the claustrum, the lateral septum
The main targets of PT were the medial frontal polar
(FPm), anterior cingulate, prelimbic, infralimbic, medial
orbital, dorsal agranular insular, piriform and entorhinal
cortices, the ventral subiculum of hippocampus, the claustrum, the core and shell of nucleus accumbens, the medial
striatum (CP), BST, and caudal parts of the central and
basal nuclei of amygdala. PT also distributes to the ventral orbital and perirhinal cortices, the dorsal subiculum
of hippocampus, lateral septum, olfactory tubercle, medial
and cortical nuclei of amygdala, RE of thalamus, and the
lateral hypothalamus.
Although there is considerable overlap in PT and PV
projections, there are several important differences between the two sets of projections. PT sends considerably
stronger projections than PV to the mPFC, to the lateral
entorhinal cortex, to the ventral subiculum, and to anterior regions of the dorsal and ventral striatum. Differences
are particularly notable with respect to the mPFC. PT
strongly targets the mPFC, distributing throughout the
ventral mPFC to the medial frontal polar, medial orbital
(MO), anterior cingulate, prelimbic and infralimbic cortices, and particularly heavily in outer layers (1 and 3) of
MO, PL, and IL (Fig. 8A–C). By contrast, the projections of
PV (PVa and PVp) to the mPFC are modest and mainly
confined to IL and PL. With respect to nucleus accumbens
(ACC), PT distributes more heavily to the rostral pole (Fig.
9) and core of ACC (Figs. 10A, 12E), but less densely to the
shell of ACC (Figs. 3B, 5A) than does PV. Unlike PVa, but
similar to PVp, PT strongly targets the dorsal striatum.
PT fibers terminate densely (and selectively) in the rostromedial CP, dorsal to the core of ACC (Fig. 10A), while
PVp distributes rostrocaudally throughout CP and heavily
to the caudal CP—a region basically devoid of fibers from
PT. Finally, in contrast to robust PV projections to virtually the entire amygdala, PT distributes significantly to
caudal, but at best modestly, to rostral parts of the amygdala (see Fig. 13B,E).
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EFFERENTS OF PV AND PT NUCLEI
Fig. 10. A,B: Low-magnification darkfield photomicrographs of
transverse sections through the forebrain depicting patterns of labeling the dorsal and ventral striatum (A) and the amygdala (B) produced by a PHA-L injection into the paratenial nucleus of the thalamus. A: Note the dense labeling, but uneven labeling (sparsely labeled
pockets) in the shell of nucleus accumbens (ACC) and the massive
labeling in the core of ACC (dorsal/dorsomedial to the anterior com-
229
missure) with a continuation of equally dense labeling into ventromedial parts of the dorsal striatum (caudate putamen, CP). B: Note
heavy labeling in parts of the lateral and basolateral nuclei, somewhat less pronounced labeling in the basomedial nucleus and an
absence of labeling in the lateral part of the central nucleus of amygdala. Scale bar ⫽ 550 ␮m for A; 500 ␮m for B. See list for abbreviations.
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230
Fig. 11. A–C: Series of rostrocaudally aligned low magnification
darkfield photomicrographs of transverse sections through the forebrain depicting patterns of labeling within the ventral subiculum
(SUBv) and lateral entorhinal cortex (ECl) produced by a PHA-L
injection into the paratenial nucleus of the thalamus. Note strong
labeling in ECl as well as in the molecular layer of SUBv. Scale bar ⫽
500 ␮m. See list for abbreviations.
PV projections: comparisons with previous
studies
As discussed, the output of PV is restricted; that is, PV
projects to a limited number of sites, but quite massively
to them. The foremost PV targets are nucleus accumbens,
bed nucleus of stria terminalis, and the amygdala.
The most complete analysis of PV projections was an
early report by Moga et al. (1995). Our findings were
comparable to theirs for the anterior PV (PVa) but differed
R.P. VERTES AND W.B. HOOVER
considerably for the posterior PV. In accord with Moga et
al. (1995), we demonstrated pronounced PVa projections
to the shell of ACC and to the central and basomedial
nuclei of amygdala, but unlike them, also described substantial PVa projections to the core of ACC as well as to
the medial, basolateral, and cortical nuclei of amygdala.
On the other hand, they demonstrated denser projections
to nuclei of the hypothalamus including the retrochiasmatic nucleus, subparaventricular zone, and the ventromedial nucleus of the hypothalamus.
With respect to PVp, however, Moga et al. (1995) reported that PVp projections were much lighter overall
than PVa projections, while we generally found the opposite: stronger PVp than PVa projections to most sites.
Further, Moga et al. (1995) described an essential lack of
PVp projections to several sites in which we observed
them including the infralimbic, piriform, perirhinal and
agranular insular cortices, the ventral subiculum, medial
regions of the striatum, posterior BLA and BMA, and most
of the hypothalamus. The reasons for these differences are
unclear but could involve differences in size and locations
of the PVp injections.
PV projections to emotional/visceral associated forebrain areas. PV distributes to several forebrain sites
associated with emotional behavior including the infralimbic cortex, the lateral septum, bed nucleus of stria
terminalis, and almost the entire amygdala—with massive projections to CEA.
In accord with present findings, previous reports, using
various tracers, have described significant PV projections
to the infralimbic cortex in rats (Berendse and Groenewegen, 1991; Conde et al., 1995; Moga et al., 1995; Bubser
and Deutch, 1998; Otake and Nakamura, 1998; Pinto et
al., 2003), mainly targeting inner layers (5/6) of IL (Berendse and Groenewegen, 1991; Pinto et al., 2003). We
recently identified labeled cells rostrocaudally throughout
PV following retrograde tracer injections in IL (Hoover
and Vertes, 2007). PV also distributes substantially to
area 25 (or the infralimbic cortex) in primates (Hsu and
Price, 2007). Moga et al. (1995) reported that PVa projects
densely, whereas PVp sparsely (or not at all) to the lateral
septum (LS). We showed that both PVa and PVp project to
LS, but similar to Moga et al. (1995) found that the major
output was from PVa. Consistent with this, Risold and
Swanson (1997) described labeled cells throughout PV
following FG injections in LS, but progressively fewer cells
at successive caudal levels of PV.
Few reports have examined PV projections to the bed
nucleus of stria terminalis (Moga et al., 1995; Van der
Werf et al., 2002). In general accord with present findings,
Moga et al. (1995) reported that PV distributes heavily to
rostral and lateral parts (subnuclei) of BST. Although the
efferent projections of BST have been fairly extensively
examined (Dong et al., 2001; Gu et al., 2003; Dong and
Swanson, 2004, 2006), to our knowledge, only a single
early report by Weller and Smith (1982) examined afferents to BST. They showed PV and PT are virtually the sole
sources of thalamic input to BST, distributing significantly to BST.
We showed that PV distributes massively throughout
the amygdala, and with the exception of parts of the
caudal amygdala, to most subnuclei of the amygdala. The
foremost PV targets are the central and basal nuclei of the
amygdala. In accord with present findings, an early examination of thalamic afferents to the amygdala (Ottersen
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
Fig. 12. A–C: Series of low-magnification brightfield photomicrographs of transverse sections through the forebrain depicting the site
of a FluoroGold injection in the shell of nucleus accumbens (ACCs) (A)
and patterns of retrogradely labeled cells within the anterior paraventricular (PV) and paratenial (PT) nuclei (B) and the posterior
paraventricular nucleus (C) produced by this injection. Note significant numbers of retrogradely labeled neurons in PT, moderate numbers in posterior PV, and relatively few in the anterior PV with this
injection. D–F: Series of low- magnification brightfield photomicro-
231
graphs of transverse sections through the forebrain depicting the site
of a FluoroGold injection in the core of nucleus accumbens (ACCs) (D)
and patterns of retrogradely labeled cells within the anterior paraventricular (PV) and paratenial (PT) nuclei (E) and posterior paraventricular nucleus (F) produced by this injection. Note significant
number of retrogradely labeled neurons in anterior PV and PT and
moderately number in posterior PV produced by this injection. Scale
bar ⫽ 500 ␮m for A,D; 350 ␮m for B,E; 400 ␮m for C,F. See list for
abbreviations.
The Journal of Comparative Neurology
232
and Ben-Ari, 1979) described widespread PV (and PT)
projections to the amygdala, stating that “the paraventricular and paratenial nuclei of the thalamus were found
to project throughout the amygdaloid complex.” Several
subsequent studies have confirmed pronounced PV projections to CEA, BMA, and BLA (Berendse and Groenewegen, 1990; Su and Bentivoglio, 1990; Turner and Herkenham, 1991; Moga et al., 1995; Peng and Bentivoglio, 2004).
PV projections to ‘cognitive-associated’ forebrain
areas. Groenewegen and colleagues (Room et al., 1985;
Groenewegen et al., 1990) initially defined a system of
connections (or loop) from the prelimbic cortex ⬎ ventral
striatum ⬎ ventral pallidum ⬎ MD of thalamus ⬎ PL
which they termed the ‘PL circuit.’ The ‘PL circuit’ has
subsequently been expanded to include several additional
structures; principal among them are the dorsal agranular insular cortex (AId), hippocampus/parahippocampus,
the basolateral amygdala, parts of midline thalamus and
the ventral tegmental area (VTA) (Vertes, 2006). PL and
its interconnected circuitry serve a recognized role in cognitive functions (Laroche et al., 2000; Groenewegen and
Uylings, 2000; Vertes, 2006). PV distributes to several
structures of prelimbic circuit: PL, AId, ACC, EC, the
ventral subiculum, BLA, and VTA.
We showed that PV (PVa and PVp) distributes: 1) selectively to IL and PL of the ventral mPFC; 2) more
heavily to PL than to IL; and 3) rostrocaudally throughout
PL, terminating most densely in inner layers of PL. These
findings are consistent with previous descriptions of significant PV projections to PL (Berendse and Groenewegen,
1991; Conde et al., 1995; Moga et al., 1995; Bubser and
Deutch, 1998; Otake and Nakamura, 1998; Pinto et al.,
2003; Hoover and Vertes, 2007).
We found that PVa and PVp distribute massively
throughout the shell and core of ACC. Although early
reports showed that PV (and PT) strongly target ACC
(Groenewegen et al., 1980; Newman and Winans, 1980;
Beckstead, 1984; Jayaraman, 1985; Phillipson and Griffiths, 1985), Groenewegen and colleagues (Berendse et al.,
1988; Berendse and Groenewegen, 1990) were the first to
show that each of the midline nuclei distribute to select,
and only partially overlapping, territories of the ventral
striatum. Regarding PV, they reported that of the midline
nuclei of thalamus, PV was the predominant source of
afferents to the shell of ACC, and while also pronounced to
the core, were shared by other midline thalamic groups to
the core (Berendse and Groenewegen, 1990). Several subsequent studies have confirmed ‘massive’ PV projections
to ACC, and further showed that a fairly significant percentage of PV fibers to ACC collateralize to other sites
(Meredith and Wouterlood, 1990; Su and Bentivoglio,
1990; Brog et al., 1993; Freedman and Cassell, 1994; Moga
et al., 1995; Bubser and Deutch, 1998; Otake and Nakamura, 1998; Erro et al., 2002; Pinto et al., 2003; Parsons et
al., 2006, 2007), mainly to the mPFC (Bubser and Deutch,
1998; Otake and Nakamura, 1998) and to the amygdala
(Su and Bentivoglio, 1990).
Finally, in accord with previous reports (Berendse et al.,
1988; Berendse and Groenewegen, 1990), we found that
PV fibers distribute in a nonhomogeneous (or ‘patch/
matrix’) manner to the nucleus accumbens; that is, regions of dense innervation interspersed with relatively
fiber free zones (Figs. 2, 3B, 4, 5A). Berendse et al. (1988)
reported that densely PV-innervated regions of the rostral
ACC and sparsely innervated areas of the caudomedial
R.P. VERTES AND W.B. HOOVER
ACC overlap with zones of strong and weak enkephalin
immunoreactivity, respectively. We did not immunostain
for enkephalin and, hence, cannot confirm these findings.
We showed that PV distributes moderately to the entorhinal cortex and to the ventral subiculum of the
hippocampus—mainly to the rostral EC/subiculum and to
ventral aspects of the subiculum, adjoining EC. Previous
reports (Berendse and Groenewegen, 1991; Moga et al.,
1995) have similarly described PV projections to EC and to
the ventral subiculum and, like here, stronger projections
from the anterior than posterior PV. Retrograde tracer
injections in the hippocampus, involving the ventral subiculum, give rise to labeled cells in PV (mainly PVa) (Wyss
et al., 1979; Riley and Moore, 1981; Su and Bentivoglio,
1990), and the hippocampus is the source of significant
return projections to PV, originating from the ventral
subiculum (Witter, 2006).
As described, the amygdala is a major PV target, with
projections heaviest to the central (CEA) and basomedial
(BMA) nuclei of amygdala. While PV projections to BLA
are less dense than to CEA and BMA, they are nonetheless pronounced, mainly targeting the posterior BLA
(BLAp), bordering BMA. Earlier reports have similarly
described marked PV projections to BLA (Ottersen and
Ben-Ari, 1979; Berendse and Groenewegen, 1990, 1991;
Su and Bentivolglio, 1990; Turner and Herkenham, 1991;
Moga et al., 1995). BLA is an integral part of the “prelimbic circuit.” BLA has strong links with PL (Sesack et al.,
1989; McDonald, 1987, 1991; McDonald et al., 1996;
Conde et al., 1995; Vertes, 2004; Gabbott et al., 2006;
Hoover and Vertes, 2007), as well as with other parts of
the circuit including the hippocampus, ACC, claustrum,
and the insular cortex (McDonald, 1987; Brog et al., 1993;
Petrovich et al., 1996; Pikkarainen et al., 1999; Majak et
al., 2002).
PV as an interface in the flow of information between
the suprachiasmatic nucleus (SCN) and other regions
of the brain. In accord with previous reports (Moga et
al., 1995; Moga and Moore, 1997; Krout et al., 2002), we
showed that PV projects moderately densely to the suprachiasmatic nucleus of the hypothalamus. SCN, in turn, is
the source of significant projections to PV (Watts et al.,
1987; Novak et al., 2000; Peng and Bentivoglio, 2004;
Zhang et al., 2006). Accordingly, PV appears to represent
an important relay in the transfer of information to and
from the SCN—the circadian pacemaker (Mistlberger,
2005; Morin and Allen, 2006). While afferents to SCN
generally serve to entrain SCN activity to light/dark conditions, PV lesions do not disrupt circadian timing or
entrainment to light (Ebling et al., 1992). This suggests a
nonphotic modulatory influence of PV on SCN. Moga et al.
(1995) proposed that PV conveys information on basal
levels of activation to the SCN—functions associated with
PV/midline thalamus (Van der Werf et al., 2002; Vertes,
2006).
Regarding SCN-PV projections, the SCN has few direct
outputs to the systems it affects (Deurveilher and Semba,
2005; Morin and Allen, 2006), indicating indirect routes to
them, possibly through PV. At the light and EM levels,
Peng and Bentivoglio (2004) showed that SCN strongly
targets PV, and further that SCN fibers synapse with PV
cells projecting to the amygdala. On this basis they concluded that PV “plays a role in the transfer of circadian
timing information to the limbic system.”
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
233
Figure 13
The Journal of Comparative Neurology
234
PT projections: comparisons with previous
studies
As discussed, there is significant overlap in PV and PT
projections. Although a few reports have described PT
projections to specific targets, to our knowledge no previous study has examined the totality of PT projections.
We showed that PT distributes densely throughout the
ventral PFC to AC, PL, IL, and medial orbital (MO) cortices, with projections heaviest to PL. In an early examination of midline and intralaminar thalamic connections
with the cortex, Berendse and Groenewegen (1991) similarly described PT projections to the mPFC, but unlike
here, projections were modest and largely confined to ventral aspects of the mPFC, mainly to MO and IL. Their PT
injection, however, was small and restricted to the medial
aspect of the anterior PT (see their fig. 1A, p. 75; Berendse
and Groenewegen, 1991). Supporting present findings,
retrograde tracer injections in AC, PL, and IL have been
shown to give rise to significant numbers of labeled cells in
PT (Conde et al., 1995; Hoover and Vertes, 2007). PT also
strongly targets the ventral mPFC in primates, mainly IL
(area 25) and PL (area 32) (Hsu and Price, 2007).
Similar to PV, ACC is a major destination of PT fibers.
In general accord with present results, two early studies
(Kelley and Stinus, 1984; Carlsen and Heimer, 1986) described robust PT projections to ACC, terminating heavily
in the medial two-thirds of ACC (shell region) with some
extension dorsally into dorsomedial aspects of CP. Berendse and Groenewegen (1990) confirmed marked PT
projections to the shell of ACC, particularly dense to the
ventromedial shell of ACC. Although they also reported
that PT distributes to the core of ACC and to the dorsomedial CP, projections were considerably less pronounced
than the presently described massive distribution of PT
fibers to the core of ACC and to the dorsomedial CP (see
Figs. 7D–F, 10A). Consistent with our results, Brog et al.
(1993) described significant numbers of labeled cells in PT
following retrograde tracer injections in the core or shell of
ACC.
As demonstrated, PT fibers mainly target caudal regions of the amygdala, predominantly the lateral and
basal nuclei of amygdala. In contrast to the dense PV
innervation of CEA, PT fibers largely avoid the core of
Fig. 13. A–C: Series of low-magnification brightfield photomicrographs of transverse sections through the forebrain depicting the site
of a FluoroGold injection in the basolateral nucleus (BLA) of the
amygdala (A) and patterns of retrogradely labeled cells within the
anterior paraventricular (PV) and paratenial (PT) nuclei (B) and the
posterior paraventricular nucleus (C) produced by this injection. Note
significant numbers of retrogradely labeled neurons in the posterior
PV but relatively few numbers in the anterior PV and PT with this
injection. D–F: Series of low-magnification brightfield photomicrographs of transverse sections through the forebrain depicting the site
of a FluoroGold injection in the central nucleus (CEA) of the amygdala
(D) and patterns of retrogradely labeled cells within the anterior
paraventricular (PV) and paratenial (PT) nuclei (E) and the posterior
paraventricular nucleus (F) produced by this injection. Note moderate
numbers of retrogradely labeled cells in anterior and posterior PV,
and relatively few in PT. Finally, note the presence of labeled neurons
in other nuclei of the midline thalamus (C,F) produced with BLA and
CEA injections; namely, in the intermediodorsal and central medial
nuclei (C) and the rhomboid and reuniens nuclei (F). Scale bar ⫽ 750
␮m for A; 300 ␮m for B; 500 ␮m for C; 700 ␮m for D; 400 ␮m for E; 450
␮m for F. See list for abbreviations.
R.P. VERTES AND W.B. HOOVER
CEA, projecting instead to the fringes of CEA. Ottersen
and Ben-Ari (1979) identified few labeled cells in PT with
retrograde injections in CEA, the cortical nuclei, or anterior regions of the basal nuclei, but described significant
numbers of reacted cells in PT following large amygdalar
injections spanning the rostral and caudal BMA/BLA.
Subsequent reports using retrograde (Su and Bentivoglio,
1990) or anterograde tracers (Turner and Herkenham,
1991) similarly demonstrated PT projections to the lateral, basomedial, and basolateral nuclei of amygdala.
We showed that PT distributes throughout entorhinal
cortex and the ventral subiculum, terminating within
fairly restricted zones of both sites: mainly inner layers
(3– 6) of the lateral EC and the molecular layer of the
ventral subiculum. Berendse and Groenewegen (1991)
demonstrated a similar distribution of PT fibers to EC and
to the ventral subiculum, but in contrast to the present
findings described stronger PV than PT projections to
these sites—we found the opposite. Differences could involve relative size and placements of injections in PT and
PV. Several reports have identified labeled cells in PT
following retrograde tracer injections in the hippocampus
(Wyss et al., 1979; Riley and Moore, 1981; Su and Bentivoglio, 1990), or entorhinal cortex (Beckstead, 1978;
Wyss et al., 1979; Insausti et al., 1987).
Functional considerations
Although the projections of PV and PT significantly
overlap, suggesting comparable functions, considerably
greater attention has been given to the functional characteristics of PV. An accumulating body of evidence indicates that PV receives inputs from several sites of the
brainstem and hypothalamus that are known to exert
activating and/or ‘wakefulness-promoting’ effects on the
forebrain. This includes afferents from monoaminergic,
cholinergic, and peptide-containing systems of the brainstem and diencephalon, prominently including orexin/
hypocretin cells of the lateral hypothalamus (Chen and
Su, 1990; Vertes, 1991; Freedman and Cassell, 1994;
Otake and Ruggiero, 1995; Peyron et al., 1998; Cutler et
al., 1999; Vertes et al., 1999; Bhatnagar et al., 2000; Krout
et al., 2002; Kirouac et al., 2005; Otake, 2005; Parsons et
al., 2006). Accordingly, PV/PT (and other nuclei of the
midline thalamus) are thought to serve an essential role in
arousal and attention (Van der Werf et al., 2002; Vertes,
2006; Vertes et al., 2006).
In line with the foregoing, PV cells show elevated levels
of c-fos expression during wakefulness (Peng et al., 1995;
Novak et al., 2000) as well as during stressful conditions,
elicited by various stressors (Chastrette et al., 1991; Bubser and Deutch, 1999; Sica et al., 2000; Otake et al., 2002).
PV appears to be critically involved in adaptive responses
to stress (Bhatnagar and Dallman, 1998; Bhatnagar et al.,
2000, 2002; Otake et al., 2002) through direct (Sawchenko
and Swanson, 1983; present results), or predominantly
indirect projections to paraventricular nucleus of the hypothalamus (Sawchenko and Swanson, 1983; Bhatnagar
and Dallman, 1998; Dong et al., 2001; Otake et al., 2002;
Dong and Swanson, 2006).
In addition to its role in promoting arousal/wakefulness,
the orexin system participates in feeding behavior (for
review, see Willie et al., 2001). Intraventricular injections
of orexin (orexin A) stimulates food consumption in satiated rats (Sakurai et al., 1998; Edwards et al., 1999;
Haynes et al., 1999), anti-orexin antibodies or receptor
The Journal of Comparative Neurology
EFFERENTS OF PV AND PT NUCLEI
antagonists suppress feeding (Haynes et al., 2000), and
orexin knockout mice are hypophagic (Hara et al., 2001).
These effects may in part be mediated the actions of orexin
on PV. Specifically, Nakahara et al. (2004) described elevated c-fos expression in PV in anticipation of feeding
(food anticipatory activity) in deprived rats, and further
reported that PV lesions attenuated anticipatory locomotor activity associated with feeding. Angeles-Castellanos
et al. (2007) similarly reported elevated c-fos expression in
PV with anticipated feeding and, interestingly, also described enhanced c-fos expression in several other limbic
forebrain structures before and immediately after the delivery of food to deprived rats, including the central and
basal nuclei of the amygdala, BST, the lateral septum,
ACC (core and shell) and the infralimbic/prelimbic cortices. As demonstrated here, these are the main forebrain
targets of PV (and PT), suggesting a PV/PT influence on
them in complex behaviors associated with feeding.
Related to this, Kelley et al. (2005) recently put forth a
model suggestive of a role for PV in motivated behaviors
as exemplified by feeding. Although not necessarily limited to feeding, the model addressed mechanisms responsible for the ingestion of palatable foods under satiated
conditions. According to Kelley et al. (2005), PV receives
diverse inputs which, among other things, code the incentive value of foods and when incentives are high (desirable
foods), feeding ensues, even in a satiated state, mainly
through the actions of PV on the ventral striatum. They
stated: “PVT may act as an interface between signals
related to arousal, energy balance, circadian or diurnal
rhythms, and reward, and major striatal motor output
systems.”
In summary, PV (and PT) receive a vast array of afferents from the brainstem, hypothalamus, and limbic forebrain and appear to serve as a critical gateway for the
transfer of multimodal information to structures of the
limbic system in the selection of appropriate responses to
changing environmental conditions. In effect, depending
on the relative dominance of sets of inputs to PV/PT,
coupled with their output to specific structures of the
limbic forebrain, PV/PT would guide behavior toward a
particular outcome among various potential outcomes.
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