Brain Struct Funct (2010) 215:1–28
DOI 10.1007/s00429-010-0249-x
ORIGINAL ARTICLE
Pattern of distribution of serotonergic fibers to the thalamus
of the rat
Robert P. Vertes • Stephanie B. Linley
Walter B. Hoover
•
Received: 31 December 2009 / Accepted: 16 March 2010 / Published online: 13 April 2010
Ó Springer-Verlag 2010
Abstract It is well established that serotonergic
(5-hydroxytryptamine, 5-HT) fibers, mainly originating
from the dorsal and median raphe nuclei of the brainstem,
distribute throughout the forebrain, most heavily to ‘limbic’ forebrain structures. Few reports have examined the
distribution of 5-HT fibers to the thalamus and none to our
knowledge using immunoprocedures for the detection of
the serotonin transporter (SERT)—a very sensitive marker
for 5-HT fibers. Using immunohistochemical methods for
SERT, we examined the pattern of distribution of 5-HT
fibers to the thalamus in the rat. We show that serotonergic
fibers are heavily concentrated in midline, intralaminar and
association nuclei of the thalamus, and with the exception
of the lateral geniculate complex, weakly distributed to
principal nuclei of thalamus. Specifically, we demonstrate
that 5-HT fibers are densely concentrated in the anteroventral, anteromedial and interanteromedial nuclei of the
anterior thalamus, the paraventricular, rhomboid and
reuniens nuclei of the midline thalamus, the central medial
and central lateral nuclei of the intralaminar thalamus, the
intermediodorsal nucleus, the lateral dorsal nucleus, and
the dorsal and ventral lateral geniculate nuclei and intergeniculate leaflet of the LGN complex. Less densely
innervated sites include the mediodorsal, paracentral,
parafascicular, lateral posterior and submedial nuclei of
R. P. Vertes (&) W. B. Hoover
Center for Complex Systems and Brain Sciences,
Florida Atlantic University, Boca Raton, FL 33431, USA
e-mail: vertes@ccs.fau.edu
S. B. Linley
Department of Psychology, Florida Atlantic University,
Boca Raton, FL 33431, USA
thalamus. Remaining regions of the thalamus, largely
consisting of principal nuclei, contained few 5-HT fibers.
This pattern of 5-HT innervation indicates that serotonin/
serotonergic fibers mainly affect thalamic nuclei with
connections to ‘non-principal’ or limbic regions of the
cortex (or forebrain). This suggests that serotonergic fibers
to the thalamus may exert a significant influence on
affective and cognitive functions, possibly complementing
the actions of 5-HT fibers to other parts of the brain
involved in emotional and cognitive behaviors.
Keywords Midline thalamus Intralaminar thalamus Lateral geniculate complex Limbic forebrain Nucleus reuniens Paraventricular nucleus of thalamus Affective behavior
Abbreviations
5-HT
5-Hydroxytryptamine, serotonin
AD
Anterodorsal nucleus of the thalamus
AM
Anteromedial nucleus of thalamus
APN
Anterior pretectal nucleus
AV
Anteroventral nucleus of thalamus
CL
Central lateral nucleus of the thalamus
CM
Central medial nucleus of thalamus
COM
Commissural nucleus, periaqueductal gray
cpd
Cerebral peduncle
DR
Dorsal raphe nucleus
ec
External capsule
EC
Entorhinal cortex
fr
Fasciculus retroflexus
fx
Fornix
HD
Head direction
HF
Hippocampus
IAD
Interanterodorsal nucleus of thalamus
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2
IAM
ic
IGL
IL
IMD
LD
LGNd
LGNv,m,l
LH
LHy
LPl,m
MB
MDc,1,m
MGN
MH
ml
MPT
MR
MRF
mt
NOT
NPC
OP
PAG
pc
PCN
PF
PFC
PH
PO
PR
PT
PVa,p
RE
RH
RSC
RT
SC
SCN
SERT
sm
SMT
SPF
st
VAL
VB
VM
ZI
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Brain Struct Funct (2010) 215:1–28
Interanteromedial nucleus of thalamus
Internal capsule
Intergeniculate leaflet
Intralaminar thalamus
Intermediodorsal nucleus of thalamus
Lateral dorsal nucleus of thalamus
Dorsal lateral geniculate nucleus
Ventral lateral geniculate nucleus, medial and
lateral divisions
Lateral habenula
Lateral hypothalamus
Lateral posterior nucleus of thalamus, lateral
and medial divisions
Mammillary bodies
Mediodorsal nucleus of thalamus, central,
lateral, and medial divisions
Medial geniculate nucleus
Medial habenula
Medial lemniscus
Medial pretectal nucleus
Median raphe nucleus
Mesencephalic reticular formation
Mammillothalamic tract
Nucleus of optic tract
Nucleus of posterior commissure
Olivary pretectal nucleus
Periaqueductal gray
Posterior commissure
Paracentral nucleus of thalamus
Parafascicular nucleus of thalamus
Prefrontal cortex
Posterior hypothalamus
Posterior nucleus of thalamus
Peri-reuniens nucleus
Paratenial nucleus of thalamus
Paraventricular nucleus of thalamus, anterior
and posterior divisions
Nucleus reuniens of thalamus
Rhomboid nucleus of thalamus
Retrosplenial cortex
Reticular nucleus of thalamus
Superior colliculus
Suprachiasmatic nucleus
Serotonin transporter
Stria medullaris
Submedial nucleus of thalamus
Subparafascicular nucleus
Stria terminalis
Ventroanterior lateral complex of thalamus
Ventrobasal complex of the thalamus
Ventral medial nucleus of thalamus
Zona incerta
Introduction
It is well recognized that serotonin-containing (5-hydroxytryptamine, 5-HT) fibers are widely distributed throughout
the neuroaxis. Although 5-HT fibers reach virtually all
areas of the forebrain, they are concentrated in limbic
regions of the forebrain (Steinbusch 1981; Jacobs and
Azmitia 1992; Halliday et al. 2004; Vertes and Linley
2007, 2008; Lowry et al. 2008a).
The majority of ascending 5-HT fibers originate from
the dorsal (DR) and median raphe (MR) nuclei of the
brainstem. Several reports have described patterns of distribution of DR/MR fibers to the forebrain. With respect to
the thalamus, early studies indicated rather limited DR/MR
projections to the thalamus (Azmitia and Segal 1978;
Moore et al. 1978; Vertes and Martin 1988) but subsequent
reports, using improved tracing techniques, showed relatively substantial DR and MR afferents to the thalamus.
DR/MR fibers mainly target ‘non-specific’ (or limbic)
nuclei of the thalamus as well as parts of the ‘visual thalamus’. This would primarily include the anterior nuclei, the
mediodorsal nucleus, the midline and intralaminar nuclei,
the habenula, the laterodorsal nucleus, and the lateral
geniculate (LGN) complex. With a few exceptions, specific
(principal) nuclei of the thalamus appear to lack input from
DR/MR (Vertes 1991; Morin and Meyer-Bernstein 1999;
Vertes et al. 1999).
In addition to 5-HT cells, the DR and MR contain other
types of ‘projection’ neurons including dopaminergic,
GABAergic, glutamatergic and various peptide containing
cells (Trulson et al. 1985; Melander et al. 1986; Austin
et al. 1997; Charara and Parent 1998; Day et al. 2004;
Waselus and Van Bockstaele 2007; Lowry et al. 2008a).
Accordingly, the extent to which DR/MR projections to the
thalamus originate specifically from 5-HT DR/MR cells
remains to be determined. Although no report has examined the overall distribution of serotonergic DR/MR fibers
to the thalamus, a few studies have described 5-HT DR/MR
projections to some nuclei of the thalamus. Specifically,
studies combining retrograde tracing with 5-HT immunostaining have demonstrated 5-HT DR or MR projections to
the anterodorsal and anteroventral nuclei of the anterior
thalamus (Gonzalo-Ruiz et al. 1995), to the lateral geniculate nucleus and intergeniculate leaflet (Villar et al. 1988;
Meyer-Bernstein and Morin 1996; Harrington 1997; Morin
and Blanchard 1999) and to the paraventricular nucleus
(Otake and Ruggiero 1995; Hsu and Price 2009).
The pattern of distribution of serotonergic dorsal and
median raphe fibers to most nuclei of the thalamus remains
largely unknown. Despite this, the finding of two early
immunohistochemical analyses, one in rats (Cropper et al.
1984) and the other in monkeys (Lavoie and Parent 1991),
Brain Struct Funct (2010) 215:1–28
showed that 5-HT fibers spread widely throughout the
thalamus. These early studies, however, used immunostaining procedures for the detection of serotonin in cells/
fibers (Steinbusch 1981), and while still a widely utilized
technique, newer immunostaining procedures have been
developed for the identification of the serotonin transporter
protein (SERT) in 5-HT fibers (Sur et al. 1996; Zhou et al.
1996). Although both methods are useful and each has its
unique advantages, Aznar and colleagues (Nielsen et al.
2006) recently reported that SERT was preferable to 5-HT
as a marker for serotonergic fibers.
In particular, they showed that serotonin only began to
approach the quality of SERT for identifying 5-HT fibers
when 5-HT immunohistochemistry was combined with
pre-treatments, particularly the use of monoamine oxidase
inhibitors (MAOIs). For instance, they reported: (1) an
approximately 200% increase in the detection of 5-HT
immunolabeled fibers in rats pre-treated with MAOIs and
(2) *90% correspondence in the co-expression of 5-HT?
and SERT? fibers in MAOI-treated rats compared to only
a 30% correspondence in non-treated rats. The latter difference (30% correspondence) was attributed to the loss (or
inability to detect) of immunostained 5-HT fibers in
untreated animals.
Consistent with Nielsen et al. (2006), we found that
5-HT and SERT immunoreactive procedures labeled a
comparable set of 5-HT fibers in the thalamus, and that
SERT produced a stronger signal than did 5-HT. Accordingly, we used SERT immunohistochemical techniques to
characterize the pattern of distribution of serotonergic
fibers to the thalamus of the rat.
In brief, we show that serotonergic fibers are densely
concentrated in midline nuclei, rostral intralaminar nuclei,
most of the anterior nuclei, the laterodorsal nucleus, and
the LGN complex. Of the midline group, 5-HT labeling
was most pronounced in the paraventricular, rhomboid and
reuniens nuclei. Although no region of the thalamus was
devoid of 5-HT fibers, labeling was very light in sensory
and motor nuclei of the thalamus and in the medial
geniculate nucleus.
3
7.4. The brains were removed and postfixed overnight in
4% paraformaldehyde in 0.1 M PB. Brains were then
placed in a 30% sucrose solution for another 48 h. Following this, 50 lm coronal sections were taken on a
freezing microtome in a one in three series: one series of
sections through the thalamus were prepared for SERT
immunohistochemistry and a second series was stained
with cresyl violet. 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.
Immunohistochemistry
SERT
Sections were initially treated with a 30-min sodium
borohydride incubation (1% in 0.1 M PB) to remove
excess aldehydes. Following a copious PB wash, sections
were incubated for 1 h in 0.5% BSA in 0.1 M Tris buffered
saline (TBS) (pH 7.6). Sections were rinsed in 0.1 M PB
and then incubated in the primary antibody, rabbit antiSERT (Immunostar, Hudson, WI) at a concentration of
1:10,000 in a diluent of 0.1% bovine serum albumin (BSA)
in TBS containing 0.25% Triton X-100 for 48 h. Following
a 0.1 M PB wash, sections were placed in a secondary
antibody solution of biotinylated goat anti-rabbit immunoglobulin (Vector Labs) at a 1:500 concentration in diluent for 2 h. This was followed by another PB wash.
Sections were then incubated for 2 h in a tertiary antibody
solution of biotinylated horse anti-goat immunoglobulin
(Vector Labs) at a 1:500 concentration in diluent. After
washing the tissue in 0.1 M PB, sections were incubated
for 60 min in a 1:200 dilution of a peroxidase–avidin
complex using the Vector Elite kit. Following a final 0.1 M
PB wash, SERT immunoreactive fibers were visualized by
placing them for approximately 3–4 min in a solution
containing 0.022% DAB (Aldrich, Milwaukee, WI) and
0.003% hydrogen peroxide in TBS. Sections were mounted
onto chrome-alum gelatin-coated slides, dehydrated using
graded methanols and coverslipped with permount.
Materials and methods
Photomicroscopy
Ten (5 male, 5 female) naı̈ve Sprague-Dawley rats (Harlan,
Indianapolis, IN) weighing 275–300 g were housed in pairs
on a 12:12 light dark cycle for 7 days during which food
and water were available ad libitum. Rats were then deeply
anesthetized with an intraperitoneal injection of sodium
pentobarbital (Nembutal, 75 mg/kg) and perfused transcardially with 30 ml of cold heparinized 0.1 M phosphate
buffer saline (PBS), followed by 200–300 ml chilled 4%
paraformaldehyde in 0.1 M phosphate buffer (PB) at pH of
For depiction of SERT and 5-HT fibers, lightfield photomicrographs at 100 times magnification were captured
throughout the extent of the thalamus from representative
cases using a Nikon DXM1200 camera mounted onto a
Nikon Eclipse E600 microscope. The individual captures
were then compiled using Image Pro-Plus 4.5 (Media
Cybernetics, Silver Springs, MD) and imported into Adobe
Photoshop (CS 2.0; Mountain View, CA) where they were
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adjusted for brightness and contrast. Representative sections throughout the thalamus were captured and illustrated. Files were imported into Adobe Illustrator (CS 2.0)
where borders were drawn around thalamic nuclei by
comparing immunostained sections to an adjacent series
of Nissl-stained sections and with the aid of the rat atlas
of Swanson (2003). Particularly noteworthy patterns of
labeling were illustrated with high magnification photomicrographs. Patterns of SERT labeling are described as
light, moderate and dense, with ‘light’ referring to a few
labeled fibers widely dispersed throughout a nucleus,
‘dense’ as a heavy concentration of labeled fibers generally
occupying a significant portion (or most) of a nucleus, and
‘moderate’ lying between these two patterns.
Results
The pattern of distribution of SERT immunoreactive fibers
in the thalamus of the rat is depicted with a series of 14
rostral to caudal transverse sections through the thalamus
(plates 1–14). We first describe patterns of labeling at each
rostral to caudal section and then compare patterns across
anatomical/functional groups of the thalamus.
A note on categories of thalamic nuclei
An early categorization of thalamic nuclei essentially
divided the thalamus into ‘relay’ nuclei and ‘non-specific’
nuclei (Dempsey and Morison 1942, 1943; Morison and
Dempsey 1942). The relay nuclei generally referred to
nuclei that transfer modality-specific information to discrete regions and layers of the cortex, while ‘non-specific’
nuclei referred to nuclei that received multimodal information and distribute to several regions of the cortex as
well as to subcortical sites. This categorization has been
revised in large part on the basis that ‘‘non-specific’’ nuclei
target very specific regions of the cortex and exhibit unique
functions (Bentivoglio et al. 1991; Groenewegen and
Berendse 1994).
Based on recent formulations (Price 1995; Groenewegen
and Witter 2004), thalamic nuclei will be categorized as
follows: (1) principal nuclei, consisting of the ventrobasal
complex (ventral posteromedial and ventral posterolateral
nuclei), the ventroanterior lateral complex, the ventromedial nucleus, the posterior nucleus, the dorsal and ventral
lateral geniculate nuclei, the intergeniculate leaflet, and the
medial geniculate nucleus; (2) association nuclei, consisting of the mediodorsal and intermediodorsal nuclei, the
submedial nucleus, the anterior nuclei (anterodorsal, anteroventral, anteromedial and interanteromedial), the lateral
dorsal nucleus and the lateral posterior nucleus; (3) midline
and intralaminar nuclei, consisting of nucleus reuniens,
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Brain Struct Funct (2010) 215:1–28
rhomboid nucleus, paraventricular nucleus, paratenial
nucleus, the central medial nucleus, paracentral nucleus,
central lateral nucleus and the parafascicular nucleus; (4)
the reticular nucleus; and (5) the epithalamus, consisting of
the medial and lateral habenula.
Plate 1 (Fig. 1a)
At the very anterior thalamus, SERT? fibers spread widely
throughout the thalamus. Prominent numbers of labeled
fibers were present in the anterior paraventricular nucleus
(PVa) and nucleus reuniens (RE) of the midline thalamus
and in the anteroventral nucleus (AV) of the anterior
thalamus whereas fewer, but still significant numbers, were
visible in the anteromedial (AM), interanterodorsal (IAD),
paratenial (PT) and reticular nuclei (RT) of thalamus. The
anterodorsal nucleus of the anterior thalamus was lightly
labeled.
Plate 2 (Fig. 1b)
As seen rostrally (Fig. 1a), PVa and RE were densely and
uniformly labeled. Within the anterior nuclei of thalamus,
AV was heavily labeled, AM, IAD and the interanteromedial nucleus (IAM) moderately labeled, and AD lightly
labeled (Fig. 2). PT and RT contained modest numbers of
SERT? fibers.
Plate 3 (Fig. 3a)
Labeled fibers continued to be heavily distributed
throughout AV, PVa, and RE—and nearly as densely within
the rostral pole of the lateral dorsal nucleus (LD). Figure 4
depicts the pattern of midline labeling, showing dense
aggregates of SERT? fibers in PVa, central medial nucleus
(CM), IAM and RE. The dorsal subnucleus of RE (arrow)
(Risold et al. 1997) contained fewer fibers than other parts
of RE (Figs. 3a, 4). Moderate numbers of SERT? fibers
were present in AM, IAD, rostral aspects of the mediodorsal
(MD) and the ventral anterior lateral complex (VAL) of
thalamus. AD, PT and RT were lightly labeled.
Plate 4 (Fig. 3b)
Significant numbers of SERT? axons were visible in AV,
PVa (strongest medially), RE and the rostral pole of LD.
Other heavily labeled sites were CM and the rhomboid
nucleus (RH) and to a lesser extent IAM. Whereas rostrally
there was a clear difference in density of labeling between
AV and the medially bordering AM and IAD, the gradients
between them were less pronounced at this level, owing to
stronger labeling of AM and IAD. Labeled fibers were
moderately packed within ventral parts of the ventral
Brain Struct Funct (2010) 215:1–28
5
Fig. 1 Photomicrographs of
rostrocaudally aligned
transverse sections through the
diencephalon showing the
pattern of distribution of SERT
immunopositive fibers at two
levels of the anterior thalamus,
plate 1 (a) and plate 2 (b). As
depicted, the anterodorsal (AD)
and paratenial (PT) nuclei were
lightly labeled, the anteromedial
(AM) nucleus was moderately
labeled, and the anteroventral
(AV), paraventricular (PV) and
reuniens (RE) nuclei were
heavily labeled. This illustrates
the general range of labeling at
these and more caudal levels
(plates 3–14) of the thalamus.
See list for abbreviations.
Scale bar a, b 400 lm
thalamus in the ventral medial nucleus (VM), but considerably less so in dorsal aspects of the ventral thalamus in
VAL. AD, PT and RT contained few SERT? fibers. There
was a marked decrease in RT labeling from that of rostral
levels.
Plate 5 (Fig. 5a)
A distinctive pattern of labeling was observed at this level.
SERT? fibers were heavily distributed along the midline
within PVa, IMD, CM, IAM, rhomboid nucleus (RH) and
RE, and two bilateral bands of labeled fibers stretched
dorsolaterally from the midline to the dorsal surface of the
brain appearing as a ‘Y’-shaped pattern of labeling. The
arms of the ‘‘Y’’ contained prominent numbers of SERT?
fibers in AM, AV and LD. On the whole, labeling was less
pronounced in MD than in the anterior or midline groups.
There was a progressive decrease in labeling from the
dorsolateral to ventromedial MD, resulting in stronger
labeling in the lateral (MDl) and central (MDc) subnuclei
of MD than in the medial MD (MDm). In a similar manner,
there is a gradual reduction in density of SERT? fibers in
the ventral thalamus, extending outward from dorsal
aspects of VAL (bordering LD/AV) to the lateral surface of
the thalamus. Accordingly, inner regions of VAL (and VM)
were moderately labeled, whereas outer parts of VAL and
the ventrobasal complex (VB) were lightly labeled. As
rostrally, RT contains few SERT? axons.
Plate 6 (Fig. 5b)
With the exception of IAM which was moderately
labeled, SERT? fibers were densely concentrated dorsoventrally along the midline in PVa, CM, RH and RE.
Labeling was about as pronounced in the paracentral (PC)
and central lateral (CL) nuclei of the intralaminar complex and in LD. This pattern of labeling is depicted in
Fig. 6 showing dense aggregates of labeled fibers in CL,
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Brain Struct Funct (2010) 215:1–28
Fig. 2 High magnification
photomicrograph of a transverse
section through the rostral
diencephalon (from left side of
plate 2, Fig. 1b) showing the
fine detail of SERT
immunopositive fibers in the
anterior thalamus. Note dense
fiber labeling in the
anteroventral (AV)
paraventricular (PV) and
reuniens (RE) nuclei of the
thalamus. See list for
abbreviations. Scale bar
150 lm
PC and LD—considerably more than present dorsomedially in MD or ventrolaterally in VAL. As observed rostrally, there was a gradual dorsal to ventral decline in
labeling from deep (inner) to superficial aspects of the
ventral thalamus (VAL to VB). VM and the medially
adjacent submedial nucleus (SMT) were moderately and
uniformly labeled. RT contained few SERT immunoreactive fibers.
Plate 7 (Fig. 7)
Three major clusters of SERT? fibers were visible at this
level: (1) a midline group, with labeling heaviest in PVa,
RH and RE and less pronounced in the intermediodorsal
nucleus (IMD); (2) an intralaminar group, with labeling
strongest in CM followed by CL and PC; and (3) the lateral
dorsal nucleus. Moderate numbers of SERT immunoreactive fibers were also present in the medial (MH) and lateral
habenula (LH) and in SMT, but relatively few were seen
throughout the vast expanse of ventral thalamus (VM,
VAL, VB) and in RT. MD was lightly to moderately
labeled which contrasted with much stronger labeling of
adjacent regions, medially (PVa, IMD, CM) and laterally
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(CL, PC). As depicted in Fig. 8, there were subtle differences in density of labeling across subdivisions of MD such
that the central nucleus (MDc) was more heavily labeled
than the medial (MDm) or lateral MD (MDl).
Plate 8 (Fig. 9)
SERT? fibers heavily invaded the midline and LD, but
were sparsely distributed over a large expanse of the ventral thalamus in VB, VAL and RT. Within midline nuclei,
labeling was densest in PVp, RH and RE, but was also
pronounced in CM. There was a gradual decline in labeling
medially to laterally in the ventral thalamus, from VM to
VAL to VB. SMT contained moderate numbers of SERT?
fibers, intermediate between those of the laterally adjacent
VM and medially bordering RH/RE. MD was moderately
labeled, with slightly more labeled fibers in MDl and MDc
than in MDm.
Plate 9 (Fig. 10)
There was a general reduction in labeling at caudal levels
of the thalamus due to the fact that a greater part of the
Brain Struct Funct (2010) 215:1–28
7
Fig. 3 Photomicrographs of rostrocaudally aligned transverse sections through the diencephalon showing the pattern of distribution of SERT
immunopositive fibers at two levels of the anterior thalamus, plate 3 (a) and plate 4 (b). See list for abbreviations. Scale bar a, b 400 lm
caudal thalamus is occupied by principal as opposed to
non-principal nuclei. Although labeling was still prominent
along the midline in PVp, IMD, CM, RH and RE, it was
less robust than seen rostrally within these nuclei and fairly
confined to a narrow band along the midline. Figure 11
shows a dense collection of labeled fibers within RE and
the dorsally adjacent RH at this level. Comparable to
midline labeling, LD was densely labeled and CL, PC and
MD (or lateral parts of MD) were moderately labeled.
Relatively few SERT? fibers were present throughout the
vast expanse of thalamus, mainly comprised of the ventral/
ventrolateral thalamus, i.e., within the posterior nucleus
(PO), VAL, VB and VM. The habenula was lightly labeled
(MH [ LH).
Plate 10 (Fig. 12)
Whereas rostrally in the thalamus labeling was described as
forming a ‘Y’-shaped configuration (plate 5, Fig. 5a), it
largely resembled a ‘T’-shaped pattern at this level. In
effect, this consisted of a vertical column of midline
labeling in MH, PVp, IMD, CM, RE, and lateral extensions
from the midline across the dorsal surface of the brain
within CL, the lateral posterior nucleus (LP), LD and the
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Brain Struct Funct (2010) 215:1–28
Fig. 4 High magnification
photomicrograph of a transverse
section through the rostral
diencephalon (from plate 3,
Fig. 3a) showing the fine detail
of SERT immunopositive fibers
in midline and adjacent nuclei at
the level of the anterior
thalamus. Note dense fiber
labeling in the paraventricular
(PV) and reuniens (RE) nuclei
of the midline thalamus and the
anteromedial (AM) and
interanteromedial nuclei of the
anterior thalamus. See list for
abbreviations. Scale bar
300 lm
dorsal lateral geniculate nucleus (LGNd). Of these sites,
labeling was densest in PVp, RE, LD and LGNd. Additionally, moderate numbers of SERT? fibers were present
in MD, PC, VM and SMT, but few were visible in most
remaining regions of the thalamus including PO, VAL, VB
and RT.
Plate 11 (Fig. 13)
As discussed, associated with the progressive switch from
midline/intralaminar and association nuclei to principal
nuclei (anterior to posterior thalamus), there was a corresponding gradual reduction in numbers of SERT? fibers.
This is further exemplified at this level. Whereas the LGN
complex (LGNd, LGNv), PVp and RE were densely
labeled, relatively few SERT? fibers were present
throughout most of the thalamus in MH, IMD, CL, LP,
MD, CM (moderately labeled) as well in PO, VB, VM and
RT (lightly labeled). PO labeling was slightly stronger at
this level than rostrally—a trend that continued caudally in
the thalamus.
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Plate 12 (Fig. 14)
Although labeling was still present along the midline
within PVp, IMD and CM, it was less pronounced at this
level than rostrally. The parafascicular nucleus (PF) lateral
to IMD was relatively densely labeled which set it off from
surrounding nuclei which were less heavily labeled. With
the exception of the LGN complex (LGNd and LGNv)
which was strongly labeled, SERT? fibers spread moderately (and homogeneously) throughout the dorsal thalamus
to MH, LH, caudal CL, and LP. By contrast with the dorsal
thalamus, the ventral thalamus (mainly composed of PO
and VB) contained few SERT? fibers—more in PO than in
VB.
Plate 13 (Fig. 15)
At the caudal pole of the thalamus (or juncture between the
diencephalon and midbrain), thalamic nuclei are mainly
located laterally/dorsolaterally, lateral to the emerging
pretectal area. Within the dorsolateral thalamus, LGNd,
Brain Struct Funct (2010) 215:1–28
9
Fig. 5 Photomicrographs of rostrocaudally aligned transverse sections through the diencephalon showing the pattern of distribution of SERT
immunopositive fibers at two levels of the mid thalamus, plate 5 (a) and plate 6 (b). See list for abbreviations. Scale bar a, b 400 lm
LGNv and the intergeniculate leaflet (IGL) were densely
labeled, PO, LP and PF were moderately labeled and VB
was lightly labeled. Figure 16 shows a dense collection of
SERT? fibers throughout the LGN complex and particularly strong within IGL and the lateral division of the
ventral LGN.
Plate 14 (Fig. 17)
The caudal extent of the thalamus consists of visual and
auditory structures. Of these, labeling was pronounced in
the LGNd, LGNv and IGL, moderate in LP and light in the
medial geniculate nucleus (MGN).
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Brain Struct Funct (2010) 215:1–28
Fig. 6 High magnification photomicrograph of a transverse section
through the diencephalon (from the right side of plate 5, Fig. 5a)
showing the fine detail of SERT immunopositive fibers in the
intralaminar and laterodorsal nuclei of the thalamus. Note the
relatively dense fiber labeling in the paracentral (PC), central lateral
(CL) and laterodorsal (LD) nuclei and comparatively lighter labeling
in the mediodorsal (MD) and ventral anterior lateral (VAL) nuclei of
thalamus. See list for abbreviations. Scale bar 300 lm
Functional/anatomical groups of the thalamus
are not considered part of the midline nuclei, per se,
include the intermediodorsal (IMD), interanteromedial
(IAM), and central medial (CM) nuclei. Whereas the entire
dorsoventral extent of the midline thalamus (including
IMD, IAM and CM) was densely labeled, labeling was
heaviest within PV, RH and RE. In marked contrast to
other midline groups, PT was lightly labeled. Although
5-HT fibers generally distributed homogeneously throughout the midline nuclei, there was some variation. Specifically, labeling was heavier in rostral than caudal regions of
PT, PV and RE, and somewhat denser in medial than
lateral aspects of PV and RE, particularly within the central
core compared to the lateral wings of RE.
Anterior nuclei
The anterior nuclei consist of the anterodorsal (AD),
anteroventral (AV), anteromedial (AM), interanterodorsal
(IAD) and interanteromedial (IAM) nuclei. On the whole,
the anterior group contained dense concentrations of 5-HT
fibers. AV was the most heavily labeled nucleus of the
anterior group and one of the most densely labeled sites of
the thalamus. Labeling was almost as prominent in AM,
IAD and IAM. By contrast, AD was lightly labeled. For the
most part, 5-HT fibers were homogeneously distributed
throughout the anterior thalamic nuclei.
Mediodorsal (MD) and intermediodorsal (IMD) nuclei
Midline nuclei
The midline nuclei consist of the paraventricular (PV),
paratenial (PT), rhomboid (RH) and reuniens (RE) nuclei.
Other nuclei lying along the midline of the thalamus which
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IMD lies on the midline and as a ‘midline-localized’ group
contained a dense concentration of 5-HT fibers—considerably more than the laterally adjacent MD. On the whole,
MD contained moderate numbers of 5-HT fibers; fewer
Fig. 7 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the mid
thalamus, plate 7. See list for abbreviations. Scale bar 400 lm
Brain Struct Funct (2010) 215:1–28
11
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12
than in bordering nuclei, medially (PV, IMD), laterally
(CL, PC), and perhaps dorsally (LH). There was a distinct
dorsolateral to ventromedial gradient in density of labeling
within the caudal two-thirds of MD resulting in denser
labeling in MDl and MDc than in MDm.
Brain Struct Funct (2010) 215:1–28
homogenously distributed rostrocaudally throughout CL, but
were more densely concentrated in lateral (adjacent to LD)
than in medial aspects of CL. In an analogous but reverse
manner, labeling was slightly denser medially in PC (on the
border with CM) than laterally in PC. PF was moderately to
heavily labeled—equivalent in density to that to CL.
Intralaminar nuclei
Reticular nucleus
The intralaminar (IL) nuclei consist of the central lateral (CL),
paracentral (PC) and central medial (CM) nuclei, rostrally,
and the parafascicular nucleus (PF), caudally. On the whole,
5-HT fibers were quite densely distributed throughout the
rostral intralaminar (IL) complex. As discussed with respect
to IMD, and perhaps owing to its position on the midline, CM
was the most heavily labeled nucleus of the rostral IL,
followed in order by CL and PC. Labeled fibers were
Fig. 8 High magnification photomicrograph of a transverse section
through the diencephalon (from the right side of plate 7, Fig. 7)
showing the fine detail of SERT immunopositive fibers in mediodorsal nucleus (MD) and surrounding regions of the thalamus. Note the
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Somewhat surprisingly, with the exception of the rostral
pole of RT which was moderately labeled, RT contained
relatively few 5-HT fibers. In fact, labeling throughout
approximately the caudal two-thirds of RT was roughly
equivalent to that of the dorsally adjacent ventrobasal
complex which was among the most sparsely labeled sites
of the thalamus.
slightly denser labeling in the central (MDc) than the medial (MDm)
or lateral (MDl) divisions of MD. See list for abbreviations. Scale bar
300 lm
Fig. 9 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the mid
thalamus, plate 8. See list for abbreviations. Scale bar 400 lm
Brain Struct Funct (2010) 215:1–28
13
123
Fig. 10 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the level of the mid
thalamus, plate 9. See list for abbreviations. Scale bar 400 lm
14
123
Brain Struct Funct (2010) 215:1–28
Brain Struct Funct (2010) 215:1–28
15
Fig. 11 High magnification photomicrograph of a transverse section
through the diencephalon (from plate 9, Fig. 10) showing the fine
detail of SERT immunopositive fibers in the reuniens (RE) and
rhomboid (RH) nuclei of the midline thalamus. Note the dense fiber
labeling in the RE and RH compared to lighter labeling in the laterally
adjacent submedial nucleus (SMT) of the thalamus. See list for
abbreviations. Scale bar 300 lm
Medial and lateral habenula (epithalamus)
Submedial nucleus (or nucleus gelatinosus)
The medial habenula was moderately and homogeneously
labeled. A rather narrow dorsomedial region of the lateral
habenula (LH), bordering MD, was moderately labeled
while remaining aspects of LH were lightly labeled.
On the whole, SMT contained moderate numbers of 5-HT
fibers. There was, however, a distinct rostral–caudal gradient in SMT labeling: the rostral two-thirds of SMT was
moderately labeled and the caudal one-third was lightly
labeled. SMT labeling was considerably less pronounced
than that of medially adjacent midline nuclei.
Lateral dorsal and lateral posterior nuclei
LD was one of the most heavily labeled nuclei of the
thalamus. The entire rostrocaudal extent of LD was densely
and quite homogeneously labeled. There was, however, a
slight dorsal to ventral gradient in intensity of LD labeling,
favoring the dorsal two-thirds of LD. Considerably, fewer
5-HT fibers were present in LP than in LD; LP was
nonetheless moderately labeled.
Ventral nuclei (VAL, VB, VM) and the posterior nucleus
(PO)
VAL is composed of the ventral anterior and ventral
lateral nuclei and VB consists of the ventral posteromedial (VPM) and ventral posterolateral (VPL) nuclei.
VB, VAL, PO, and VM are major principal nuclei of the
123
Fig. 12 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the caudal thalamus,
plate 10. See list for abbreviations. Scale bar 400 lm
16
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Brain Struct Funct (2010) 215:1–28
Fig. 13 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the caudal thalamus, plate 11.
See list for abbreviations. Scale bar 400 lm
Brain Struct Funct (2010) 215:1–28
17
123
Fig. 14 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the caudal thalamus, plate 12. See list
for abbreviations. Scale bar 400 lm
18
123
Brain Struct Funct (2010) 215:1–28
Fig. 15 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the caudal thalamus, plate 13.
See list for abbreviations. Scale bar 400 lm
Brain Struct Funct (2010) 215:1–28
19
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20
Brain Struct Funct (2010) 215:1–28
Fig. 16 High magnification
photomicrograph of a transverse
section through the caudal
diencephalon (from just rostral
to the left side of plate 13,
Fig. 15) showing the fine detail
of SERT immunopositive fibers
in the lateral geniculate nucleus
(LGN) complex. Note the strong
fiber labeling in all three
divisions of the LGN complex,
the dorsal (LGNd) and ventral
(LGNv) nuclei and the
intergeniculate leaflet (IGL) and
particularly dense labeling in
the lateral part of LGNv
(LGNvl) and IGL. See list for
abbreviations. Scale bar
250 lm
thalamus. With the possible exception of parts of VM
which were moderately labeled, the ventral thalamus and
PO were lightly labeled. 5-HT fibers were heterogeneously distributed throughout VM, with a marked variation in density found rostrocaudally in VM. The rostral
half of VM was moderately labeled; the caudal half
was sparsely labeled. Additionally, labeling was heavier
medially than laterally in VM. Overall, VAL was lightly
labeled, with a stronger concentration of 5-HT fibers
rostrally than caudally as well as dorsally than ventrally
in VAL. VB was one of the most sparsely innervated
sites of the thalamus, and unlike other regions of the
ventral thalamus, showed little diversity (heterogeneity)
in strength of labeling across the expanse of the nucleus.
PO labeling was also generally light but more pronounced than that of VB.
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Medial and lateral geniculate nuclei
The LGN complex was among the most densely labeled
sites of the thalamus. Significant numbers of 5-HT fibers
were present in all nuclei of the LGN complex: the dorsal
and ventral LGN and the intergeniculate leaflet. Labeling
was, however, denser in IGL and the lateral division of
LGNv than in LGNd. By contrast with the LGN complex,
MGN was lightly and homogeneously labeled.
Discussion
The present report describes the pattern of distribution of
serotonergic fibers to the thalamus in the rat using antisera
for SERT. As demonstrated, there is significant variation in
Fig. 17 Photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of SERT immunopositive fibers at the caudal thalamus, plate 14. See
list for abbreviations. Scale bar 400 lm
Brain Struct Funct (2010) 215:1–28
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22
the density of 5-HT-labeled fibers across nuclei of the
thalamus. On the whole, the thalamus could be partitioned
into regions of high and low density 5-HT innervation
corresponding on the one hand to midline/intralaminar and
association nuclei, and on the other, to principal nuclei of
the thalamus.
Serotonergic fibers distribute: (1) densely to the anteroventral, anteromedial and interanteromedial nuclei of
the anterior thalamus, the paraventricular, rhomboid and
reuniens nuclei of the midline thalamus, the central medial
and central lateral nuclei of the intralaminar thalamus, the
intermediodorsal nucleus, the lateral dorsal nucleus, and
the dorsal and ventral lateral geniculate nuclei and intergeniculate leaflet of the LGN complex; (2) moderately to
the paratenial, mediodorsal, paracentral, parafascicular,
lateral posterior and submedial nuclei; and (3) lightly to
remaining regions of the thalamus, largely consisting of
principal nuclei of the thalamus. The latter sites include
the posterior nucleus, the ventral anterior lateral complex,
the ventral medial nucleus, the ventral basal complex, the
reticular nucleus, and the medial geniculate nucleus. This
pattern of 5-HT innervation suggests that serotonin/serotonergic fibers primarily affect anterior, midline and
intralaminar nuclei of thalamus—and consequently their
limbic forebrain targets.
Comparisons with previous examinations of 5-HT
innervation of the thalamus
Two previous reports, one in the rat (Cropper et al. 1984)
and the other in the monkey (Lavoie and Parent 1991),
described patterns of distribution of 5-HT fibers to the
thalamus. As discussed, these studies used immunostaining
procedures for serotonin which are reportedly less sensitive
than those for SERT for the identification of 5-HT fibers
(Nielsen et al. 2006).
Cropper et al. (1984) described a similar pattern of 5-HT
innervation of the thalamus as demonstrated here—with
some notable exceptions. Consistent with present findings,
they described relatively dense concentrations of 5-HT
fibers in the anteroventral nucleus, the midline thalamus
(PV, RH and RE), the lateral dorsal nucleus and the ventral
part of LGN, but few in somatomotor (VAL and VB) and
auditory (MGN) regions of the thalamus. Unlike our
results, however, they indicated that labeling was light in
several nuclei presently shown to be heavily labeled
including MD, AM, CM, SMT (nucleus gelatinosus) and
LGNd. For instance, they reported that MD and AM contained few immunoreactive fibers which contrast with our
demonstration of pronounced labeling in these cell groups.
Finally, several sites were omitted from their description of
labeling such as IAM, IMD, the intergeniculate leaflet, and
the medial habenula—all of which were moderately to
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Brain Struct Funct (2010) 215:1–28
densely labeled in the present study. These differences
could, in part, involve the superior sensitivity of immunoprocedures for SERT compared to those for serotonin
in the detection of 5-HT fibers (see ‘‘Introduction’’ and
Nielsen et al. 2006).
The pattern of distribution of 5-HT fibers to the thalamus in the monkey (Lavoie and Parent 1991) was in some
respects very similar, but in others, quite different than
presently shown for the rat. Specifically, in accord with us,
Lavoie and Parent (1991) demonstrated that 5-HT fibers in
monkeys strongly targeted the midline and intralaminar
nuclei of thalamus. They stated: ‘‘The densest 5-HT
innervation of the thalamus was observed in nuclei located
directly on the midline’’ (Lavoie and Parent 1991). By
comparison with the rat, midline nuclei of the squirrel
monkey consist of three main groups: the paraventricular,
central and reuniens nuclei. The central nucleus is located
between PV and RE, and depending on rostrocaudal levels,
this region would be comparable to IAM, IMD, or the
rhomboid nucleus in the rat. The central medial nucleus
(CM) in monkeys lies ventral to the central nucleus. All
cell groups lying along the midline (PV, central, CM and
RE) contained dense concentrations of 5-HT fibers in the
monkey.
Like here, Lavoie and Parent (1991) drew particular
attention to marked differences in overall density of
labeling between ‘non-specific’ and ‘relay’ nuclei of thalamus, noting that the ‘‘non-specific nuclei received the
heaviest innervation’’ and ‘‘by comparison the more specific relay nuclei and associated nuclei were less densely
labeled’’.
By contrast with present findings, however, Lavoie and
Parent (1991) reported that the reticular nucleus was one of
the most densely labeled sites of the thalamus (with
labeling comparable to that of midline and intralaminar
nuclei) and that AV, LD, LGNd, and the habenular complex were weakly labeled. The medial and lateral habenula
were described as the most poorly innervated sites of the
thalamus. This contrasts with our demonstration that RT
(or the caudal RT) was lightly labeled and AV, LD, MH
and LGNd were heavily labeled. These discrepancies likely
involve species differences.
In a report primarily devoted to an examination of
ascending MR and DR projections, Morin and MeyerBernstein (1999) also described patterns 5-HT innervation
of the forebrain (including the thalamus) in hamsters.
Consistent with present results, Morin and Meyer-Bernstein (1999) described a sharp decreasing gradient of
labeling in the transition from non-principal to principal
nuclei of the thalamus—or in their terms, a dense serotonergic ring of labeling surrounding ‘‘a sparsely innervated
core consisting of the posterior and ventral nuclear complexes and the reticular nucleus’’. More specifically, Morin
Brain Struct Funct (2010) 215:1–28
and Meyer-Bernstein (1999) reported that labeling was
prominent along the midline within PV, IMD, CM, RH,
and RE, in MH, in parts of the intralaminar thalamus (CM
and PF), and in the LGN complex. By contrast with them,
we observed considerably denser labeling in the anterior
nuclei, LD, LP and RH, but lighter labeling in PT.
The foregoing indicates, then, that 5-HT fibers of various species (hamster, rat and monkey) strongly target
midline/intralaminar and association nuclei of the thalamus, and excluding the LGN complex, distribute lightly to
principal nuclei of the thalamus. Some species differences
exist with respect to the innervation of the visual-associated lateral nuclei (LD and LP), the habenula and RT, but
for the rat we found that LD was densely labeled, LP, MH
and LH moderately labeled and RT lightly labeled.
Correspondence between 5-HT innervation
of the thalamus and DR/MR projections to the thalamus
Generally consistent with present findings, previous
examinations of DR and MR projections (Vertes 1991;
Jacobs and Azmitia 1992; Morin and Meyer-Bernstein
1999; Vertes et al. 1999; Vertes and Linley 2007, 2008)
demonstrated that DR/MR fibers: (1) predominantly target
non-principal nuclei of the thalamus; (2) generally avoid
the central core of the thalamus including VAL, PO, VB
and VM; and (3) distribute lightly to RT.
Despite this correspondence, several regions of the
thalamus presently shown to contain relatively dense concentrations 5-HT fibers do not appear to receive significant
projections from DR or MR. These primarily include the
anterior nuclei, LP, LD, and parts of the LGN complex. It
seems possible that the anterograde tracers of earlier
reports were not optimally placed within subregions of DR/
MR giving rise to 5-HT projections to these thalamic sites.
In this regard, DR projections to LGN and LP appear to
almost entirely arise from the lateral wings of DR (Villar
et al. 1988; Waterhouse et al. 1993), those to IGL from
rostral aspects of DR (Meyer-Bernstein and Morin 1996)
and those to the anterior thalamus (AD and AV) from
ventromedial and ventrolateral regions of the rostral DR
(Gonzalo-Ruiz et al. 1995).
It could also be the case that the serotonergic innervation of thalamus may, at least in part, originate from 5-HT
neurons lying outside of DR/MR within rostral raphe nuclei
such as the supralemniscal nucleus (Vertes and Crane
1997) or caudal raphe nuclei (Peschanski and Besson 1984;
Krout et al. 2002). Finally, for some thalamic groups such
as CL and PF, DR/MR projections appear to exceed the
5-HT innervation. This suggests non-serotonergic DR/MR
projections to these sites.
23
Serotonergic innervation of nuclei lying along
the midline of the thalamus (PV, PT, IMD, IAM,
CM, RH, RE)
As described, the midline nuclei of the thalamus (PV, PT,
RH, RE), as well as other groups lying along the midline
but not classified as midline nuclei (IMD, IAM, CM),
contained dense concentrations of 5-HT fibers. Of these
nuclei, PV, CM and RE were the most heavily labeled; by
comparison PT was lightly labeled.
Unlike principal nuclei of the thalamus that target specific sensory/motor regions of the cortex, the midline nuclei
distribute almost exclusively to limbic subcortical and
cortical sites (Berendse and Groenewegen 1990, 1991; Su
and Bentivoglio 1990; Wouterlood et al. 1990; Bentivoglio
et al. 1991; Groenewegen and Berendse 1994; Van der
Werf et al. 2002; Vertes 2006; Vertes et al. 2006; Li and
Kirouac 2008; Vertes and Hoover 2008). Accordingly, the
midline nuclei occupy a pivotal position within limbic
forebrain circuitry; i.e., they receive a diverse array of
afferent projections (Krout et al. 2002; Van der Werf et al.
2002; McKenna and Vertes 2004; Kirouac et al. 2005,
2006) and distribute to restricted sets of (limbic) forebrain
structures which appear largely unique for each midline
nucleus (for review, Vertes 2006).
Among its functions, the midline thalamus is thought to
exert an activating or arousing effect on the limbic forebrain (Van der Werf et al. 2002; Vertes 2006). Regarding
the possible functional role of serotonergic afferents to the
midline thalamus, 5-HT fibers may represent a source of
excitatory drive to the midline thalamus in arousal/attention or alternatively may gate (enhance or impede) the flow
of information through the midline thalamus to other parts
of the limbic forebrain (Vertes 2006).
With respect to activating influence on the forebrain, the
dorsal raphe nucleus (and possibly MR) reportedly forms
part of a widespread ‘waking system’ of the brain that also
includes other monoaminergic nuclei, cholinergic cells of
the dorsolateral pontine tegmentum, and orexinergic neurons of the lateral hypothalamus (Saper et al. 2005a, b;
Datta and MacLean 2007). A primary, but not sole, forebrain target for DR effects on arousal/wakefulness appears
to be the paraventricular nucleus of the midline thalamus.
PV is reciprocally connected with the suprachiasmatic
nucleus (SCN) (Moga et al. 1995; Novak et al. 2000a; Peng
and Bentivoglio 2004; Li and Kirouac 2008; Vertes and
Hoover 2008) and distributes strongly to the dorsomedial
nucleus of the hypothalamus (Vertes and Hoover 2008)—a
critical hub in sleep–wake control (Saper et al. 2005a, b).
PV cells show elevated levels of c-fos expression during
wakefulness (Peng et al. 1995; Novak et al. 2000b).
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24
Anterior nuclei of the thalamus: anterodorsal,
anteroventral, anteromedial and interanteromedial
nuclei
Serotonergic fibers were densely concentrated in the anterior nuclei of the thalamus. The anteroventral nucleus of
thalamus was most heavily labeled, followed by AM and
IAM and then AD. Comparatively, AD was lightly labeled.
It is well documented that lesions of the anterior thalamus in rats produce deficits in spatial learning, or specifically in tasks utilizing allocentric cues—or allocentric
spatial learning (Aggleton et al. 1996; Byatt and DalrympleAlford 1996; Warburton et al. 1997; van Groen et al.
2002a). By contrast, lesions of structures bordering the
anterior thalamus including the mediodorsal or intralaminar
nuclei fail to produce spatial deficits (Mitchell and
Dalrymple-Alford 2005). The involvement of the anterior
nuclei in spatial behavior has been attributed to its close
connections with the hippocampus (Amaral and Witter
1995; Aggleton and Brown 1999). Aggleton and colleagues
have, in fact, proposed that the anterior thalamus forms part
of an extended network subserving hippocampal-dependent
memory, notably episodic memory in humans (Aggleton
and Brown 1999, 2006). Supporting this, alterations of the
anterior thalamus in humans produce the same severe deficits in episodic memory (diencephalic amnesia) as found
with hippocampal damage (von Cramon et al. 1985; GraffRadford et al. 1990; Van der Werf et al. 2000, 2003a, b).
Two parallel but separate sub-circuits have been identified within interconnected nuclei that were originally
described as forming Papez’s circuit (Papez 1937): a head
direction (HD) circuit and a theta rhythm circuit (Vann and
Aggleton 2004; Vertes et al. 2001, 2004; Vann 2009).
Within the anterior thalamus, HD cells are present in AD,
and ‘theta cells’ mainly in AV (Taube 1998, Vann and
Aggleton 2004; Vertes et al. 2004). It has been suggested
that theta bursting AV neurons may promote the transfer of
head direction information from AD to the retrosplenial
cortex thereby supporting spatial navigation/learning
(Vertes et al. 2004). As described, AV contains a dense
concentration of 5-HT fibers—among the heaviest in the
thalamus. Serotonergic input to AV could amplify the
effects of theta on HD circuitry. In this regard, theta
rhythmically firing neurons have been identified in DR and
MR, and may excite/drive ‘theta cells’ of AV (Kocsis and
Vertes 1992, 1996; Kocsis et al. 2006; Vertes 2010).
The rostral intralaminar nuclei (CL, PC and CM),
and the intermediodorsal (IMD) and mediodorsal (MD)
nuclei
As a group, the rostral intralaminar nuclei contain dense
concentrations of 5-HT fibers, but fewer than present in the
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Brain Struct Funct (2010) 215:1–28
midline nuclei or AV. The central medial nucleus was
heavily labeled; PC and CL were moderately labeled.
There was a mediolateral gradient in density of labeling in
the intralaminar complex (CM [ PC/CL) as well as in
IMD and MD (IMD [ MD). MD contained moderate
numbers of 5-HT fibers.
Consistent with dense labeling of midline nuclei, the
midline ‘located’ CM and IMD contained strong concentrations of 5-HT fibers—denser than the laterally situated
cell groups of these complexes. This could involve the fact
that these medial nuclei (CM and IMD) mainly target
limbic forebrain structures, whereas the lateral cell groups
(PC/CL and central/lateral MD) primarily distribute to
motor regions of the forebrain (Van der Werf et al. 2002;
Groenewegen and Witter 2004; Vertes et al. 2006).
The intralaminar (IL) and MD complexes differ from
the anterior thalamus by their virtual lack of connections
with the hippocampus and parahippocampal structures
(Berendse and Groenewegen 1991; Van der Werf et al. 2002;
Groenewegen and Witter 2004). As such, the IL thalamus
(as well as MD/IMD) do not appear to participate in hippocampal-dependent functions, but rather are involved
in prefrontal cortical-associated behaviors. Specifically, IL
or MD lesions produce little or no alteration on tasks
involving spatial memory (Hunt and Aggleton 1998a;
Bailey and Mair 2005; Mitchell and Dalrymple-Alford
2005; Wolff et al. 2008), but severely disrupt performance
on ‘prefrontally associated’ tasks, or those requiring shifts
in strategy or behavioral flexibility (Beracochea et al. 1989;
McAlonan et al. 1993; Hunt and Aggleton 1998b; Lacroix
et al. 2002; Floresco et al. 2008; Ghods-Sharifi et al. 2008;
Dolleman-van der Weel et al. 2009). The pronounced 5-HT
input to IL and MD/IMD could serve to coordinate the
activity of medial affective (CM and IMD) and lateral
motor (PC, CL and lateral MD) components of these systems, thereby providing emotional drive for complex motor
acts.
Lateral dorsal nucleus (LD) and the lateral geniculate
complex
Serotonergic fibers were densely concentrated in the lateral
dorsal nucleus and in the LGN complex: the dorsal and
ventral lateral geniculate nuclei and the intergeniculate
leaflet. Labeling was heaviest in IGL and LGNlv of the
LGN complex.
5-HT fibers were more heavily distributed within the
rostral than in the caudal LD. Rostral LD borders the
anterior nuclei and has been anatomically and functionally
linked with the anterior group (Groenewegen and Witter
2004; Jones 2007). Like the anterior nuclei, rostral LD is
strongly reciprocally connected with the retrosplenial cortex and subiculum (of hippocampus) (van Groen and Wyss
Brain Struct Funct (2010) 215:1–28
1992; Groenewegen and Witter 2004; Shibata and Naito
2007), contains head direction cells (Mizumori and
Williams 1993), and participates in spatial learning/memory
(Mizumori et al. 1994; Wilton et al. 2001; van Groen et al.
2002b). Unlike the anterior nuclei, however, LD receives
fairly substantial input from subcortical visual structures
(Thompson and Robertson 1987; Kolmac et al. 2000). The
convergence of limbic and visual information in the lateral
dorsal nucleus has led to the suggestion that LD participates in visually guided spatial navigation/learning
(Mizumori et al. 1994; van Groen et al. 2002b; Bezdudnaya
and Keller 2008). The prominent serotonergic input to LD,
particularly to the rostral LD, may sharpen visuospatial
processing during conditions requiring focused attention.
The LGN complex in the rat consists of LGNd, LGNv
and IGL. LGNd is the main relay nucleus of the LGN
complex, conveying visual information from the retina to
the visual cortex (Price 1995; Groenewegen and Witter
2004). By comparison, the LGNv and IGL receive retinal
inputs (as well as afferents from several other nuclei of the
visual system) and do not project to visual cortices, but
rather to various visual and ‘non-visual’ structures of the
forebrain and brainstem (Kolmac and Mitrofanis 2000;
Moore et al. 2000; Vrang et al. 2003; Horowitz et al. 2004).
Among its sites of distribution, the LGNv projects significantly to midline (PV, RH and RE) and lateral nuclei (LP
and LD) of the thalamus (Kolmac et al. 2000; Moore et al.
2000). The visual information reaching these structures
would appear to participate in visually guided spatial
behavior (LP/LD) or visually elicited shifts in attention
(PV/RH/RE).
The LGNv consists of a lateral, magnocellular part and a
medial parvicellular division. Based in part on differential
sets of inputs and outputs (Kolmac and Mitrofanis 2000;
Kolmac et al. 2000), the lateral and medial LGNv have
been characterized, respectively, as visual (lateral) and nonvisual (medial) divisions of the LGNv complex (Kolmac
et al. 2000). As described, we showed that 5-HT fibers
were much more densely concentrated in the lateral than in
the medial LGNv, suggesting a greater serotonergic influence on LGNv-mediated visual than non-visual functions.
LGNd and LGNv receive afferent projections from the
dorsal raphe nucleus (Villar et al. 1988; Kolmac and Mitrofanis 2000; Horowitz et al. 2004). The serotonergic
input to LGNd may modulate the transfer of signals from
the retina to the visual cortex, whereas that to LGNv (and
hence to its targets in the midline and lateral thalamus) may
amplify the effect of visual information on spatial and
attentional processing.
The IGL receives afferents from photosensitive melanopsin containing neurons of the retina and in turn
projects to the suprachiasmatic nucleus (SCN) of the
hypothalamus (Moore et al. 1995, 2000; Vrang et al.
25
2003; Horowitz et al. 2004). This indirect route from the
retina to SCN via IGL appears to fine-tune the effects of
light on circadian rhythmicity (Moore et al. 2000). For
instance, Morin and Pace (2002) demonstrated that neurotoxic lesions of IGL in hamsters significantly attenuated
(by 50%) the lengthened circadian period produced by
constant light.
IGL receives significant 5-HT (and non-5-HT) projections from the dorsal raphe nucleus (Meyer-Bernstein and
Morin 1996; Horowitz et al. 2004), and DR stimulation has
been shown to produce circadian phase shifts, mediated by
the IGL (Glass et al. 2000). Glass et al. (2000) proposed
that based on its (DR) ‘‘functional linkages to the SCN and
intergeniculate leaflet, the DR could serve to provide
behavior/arousal state information to various sites comprising the brain circadian system’’.
Summary and conclusions
In summary, serotonergic fibers were found to be densely
concentrated in the midline/intralaminar and association
nuclei of the thalamus, and with the exception of the LGN
complex, sparsely distributed within principal nuclei and
the reticular nucleus of the thalamus. Specifically, substantial numbers of 5-HT fibers were present in the midline
nuclei (PV, RH, RE), the anterior nuclei (AV, AM, IAM),
the intralaminar nuclei (CM, PC, CL), mediodorsal
nucleus, lateral nuclei (LD, LP) and the medial and lateral
habenula. With a few exceptions, these structures might be
appropriately classified as the ‘limbic thalamus’; i.e., a
constellation of thalamic nuclei that predominantly target
limbic forebrain structures that subserve affective/cognitive functions. Accordingly, through actions on the ‘limbic
thalamus’, serotonin/serotonergic axons may exert a significant modulatory influence on emotional and cognitive
aspects of behavior, complementing 5-HT effects on other
forebrain structures involved in these functions (Cassel and
Jeltsch 1995; Cools et al. 2008).
This is consistent with the role of serotonin in a host of
‘limbic’ functions as well as its well recognized involvement in affective disorders (Jacobs and Azmitia 1992;
Cools et al. 2008; Lowry et al. 2008b). Although the precise role served by serotonin in emotional and cognitive
behaviors remains to be fully determined, the present
findings showing that 5-HT fibers distribute densely to the
midline nuclei of thalamus suggest that serotonin may play
an important role in functions associated with the midline
thalamus such arousal/attention and response selection
(Vertes 2006).
Acknowledgments This research was supported by National Science Foundation grant IOS 0820639 to RPV.
123
26
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