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46
Ann. N.Y. Acad. Sci. 1018: 46–57 (2004). © 2004 New York Academy of Sciences.
doi: 10.1196/annals.1296.005
Anatomic and Functional Topography
of the Dorsal Raphe Nucleus
JOLANE K. ABRAMS, PHILIP L. JOHNSON, JACOB H. HOLLIS,
AND CHRISTOPHER A. LOWRY
University Research Centre for Neuroendocrinology, University of Bristol,
Bristol BS2 8HW, UK
A
BSTRACT
: Serotonergic systems play an important and generalized role in
regulation of sleep–wake states and behavioral arousal. Recent
in vivo
electro-
physiologic recording studies in animals suggest that several different subtypes
of serotonergic neurons with unique behavioral correlates exist within the
brainstem raphe nuclei, raising the possibility that topographically organized
subpopulations of serotonergic neurons may have unique behavioral or physi-
ologic correlates and unique functional properties. We have shown that the
stress-related and anxiogenic neuropeptide corticotropin-releasing factor can
stimulate the
in vitro
neuronal firing rates of topographically organized sub-
populations of serotonergic neurons within the dorsal raphe nucleus (DR).
These findings are consistent with a wealth of behavioral studies suggesting
that serotonergic systems within the DR are involved in the modulation of on-
going anxiety-related behavior and in behavioral sensitization, a process whereby
anxiety- and fear-related behavioral responses are sensitized for a period of up
to 24 to 48 h. The dorsomedial subdivision of the DR, particularly its middle
and caudal aspects, has attracted considerable attention as a region that may
play a critical role in the regulation of acute and chronic anxiety states. Future
studies aimed at characterization of the molecular and cellular properties of
topographically organized subpopulations of serotonergic neurons are likely to
lead to major advances in our understanding of the role of serotonergic systems
in stress-related physiology and behavior.
K
EYWORDS
: fear; anxiety; anatomy; stress; serotonin; 5-hydroxytryptamine;
5-HT; topographic
INTRODUCTION
Serotonergic systems within the brainstem raphe complex are topographically or-
ganized with respect to their anatomic and functional properties. This anatomic and
functional specificity raises the possibility that topographically organized subpopu-
lations of serotonergic neurons may have unique stress-related functional properties.
Although there are clear differences between the anatomic and functional properties
of the dorsal raphe nucleus (DR) and the median raphe nucleus (MnR),
1
in this re-
view we focus on the anatomic and functional topographic organization within the
Address for correspondence: Jolane K. Abrams, University Research Centre for Neuroendo-
crinology, University of Bristol, Marlborough Street, Bristol BS2 8HW, United Kingdom. Voice:
+
44 (0) 117-928-2181; fax:
+
44 (0) 117-928-2080.
e-mail: J.K.Abrams@bristol.ac.uk
47ABRAMS
et al.
: TOPOGRAPHY OF SEROTONERGIC SYSTEMS
DR, a brainstem raphe nucleus that contains an extensive group of serotonergic neu-
rons (estimated to number 235,000 in the human brain
2
) projecting in a topographi-
cally organized manner to forebrain and brainstem targets. Recent technical
advances have demonstrated that although the DR has been defined as a single nu-
cleus by cytologic criteria, it comprises multiple subdivisions that differ with respect
to the characteristics of individual serotonergic neurons found within them. Topo-
graphically organized subpopulations of serotonergic neurons within the DR differ
in their morphologic features, membrane and cellular properties, afferent regulation,
and efferent projection patterns. In this review, we evaluate whether or not these dif-
ferences among subpopulations of serotonergic neurons have important implications
for neural mechanisms underlying serotonergic modulation of stress-related physi-
ology and behavior. In addition, we provide atlases of the rat and mouse DR and a
proposed nomenclature that may prove valuable for future studies exploring the fine
anatomic and functional topography of this nucleus.
SEROTONERGIC NEURONS IN DIFFERENT SUBDIVISIONS OF THE
DR HAVE UNIQUE MORPHOLOGIC AND CELLULAR FEATURES
Serotonergic neurons in the rat DR appear in topographically organized groups
of small round cells, medium-sized fusiform and bipolar cells, large fusiform cells,
and very large multipolar cells.
3
Similarly, serotonergic neurons in the human DR
appear in topographically organized groups of round, ovoid, fusiform, and multi-
polar cells.
2
Although we cannot predict functional properties of serotonergic cells
based on morphologic features, the fact that serotonergic neurons with different mor-
phologic features are topographically organized within different subdivisions of the
DR suggests a potential link between structure and function. Recently developed and
recently optimized technical approaches, such as whole-cell patch-clamp electro-
physiologic studies in visualized brain slices, should allow us to begin to investigate
structure–function relationships.
In addition to regional differences in the morphology of topographically organized
subpopulations of serotonergic neurons, immunohistochemical co-localization studies
have demonstrated that topographically organized subpopulations of serotonergic neu-
rons co-express different neurotransmitters, neuropeptides, or other proteins. For ex-
ample, recent studies have identified a subpopulation of serotonergic neurons within
the dorsomedial subdivision of the DR (~
−
8.00 mm bregma) that also expresses cor-
ticotropin-releasing factor (CRF).
4
This same study revealed, consistent with previous
studies,
5
that this region of the DR projects to the central nucleus of the amygdala
(CeA), a stress-related forebrain structure that is part of a distributed central autonomic
control system. These observations, along with the high expression of neurokinin-1
immunoreactivity on neuronal fibers within the dorsomedial DR, suggest that this sub-
division may play a role in serotonergic modulation of stress-related physiology and
behavior in rats and in stress-related neuropsychiatric disorders in humans.
EFFERENT PROJECTIONS ARISING FROM THE DR
ARE TOPOGRAPHICALLY ORGANIZED
The midbrain raphe nuclei, including the DR and the MnR, are the main sources
of serotonergic innervation of forebrain stress circuits.
1
The most consistent finding
48 ANNALS NEW YORK ACADEMY OF SCIENCES
in anatomic studies is that serotonergic neurons within the DR are organized topo-
graphically in the rostrocaudal plane. That is, serotonergic neurons located more ros-
trally project selectively to specific forebrain sites (e.g., the caudate putamen,
substantia nigra, and virtually all neocortical regions), whereas serotonergic neurons
located more caudally project to other forebrain sites (e.g., the septum, hippocam-
pus, and entorhinal cortex
3,6–8
). Serotonergic neurons that project to the caudate
putamen do not project to the hippocampus, and vice versa.
9
These simple anatomic
observations suggest that topographically organized subpopulations of serotonergic
neurons have unique functional properties associated with modulation of specific
forebrain systems.
SEROTONERGIC NEURONS GIVE RISE TO COLLATERAL
PROJECTIONS TO FUNCTIONALLY RELATED TARGETS
The use of multiple retrograde tracers in a single animal has led to the proposal
that not only are serotonergic neurons topographically organized within the mid-
brain and pontine raphe nuclei, but that individual serotonergic neurons give rise to
collateral (branched) projections to functionally related targets, such as those in-
volved in stress responses.
1
These collateral serotonergic projections could allow
temporally coordinated modulation of specific neural circuits, such as those impli-
cated in central autonomic control, anxiety, and conditioned fear, which include the
CeA and the paraventricular nucleus (PVN) of the hypothalamus.
1
Collateral projec-
tions from serotonergic neurons innervating the CeA and PVN are located primarily
in medial regions of the middle DR and in bilateral clusters of cells near the cerebral
aqueduct more caudally.
5,10
These double retrograde-tracing studies and others
10–13
provide clear evidence for an anatomic topography within the DR and suggest that
individual serotonergic neurons give rise to functionally related target structures,
providing an anatomic basis for serotonergic modulation of distributed functional
systems within the brain.
AFFERENT PROJECTIONS INNERVATING THE DR
ARE TOPOGRAPHICALLY ORGANIZED
Different subdivisions of the DR receive afferent input from different sources. Ret-
rograde and anterograde studies provide evidence for specific afferents to the ventral
and dorsal parts of the middle (~
−
8.00 mm bregma) DR, the rostral DR (~
−
7.30 mm
bregma), and the ventrolateral DR.
14,15
A recent immunohistochemical study in rats
found that CRF-ir fibers in the DR are organized along a rostral-to-caudal gradient and
that CRF-ir fibers innervating different subdivisions of the DR have different propor-
tions of excitatory versus inhibitory synaptic specializations, with the majority of syn-
apses between CRF-ir terminals and dendrites in the dorsolateral DR being excitatory
and the majority of those in the ventromedial region being inhibitory.
16
Although the
origin of the full complement of CRF-ir fibers innervating the DR is uncertain, a pro-
portion of CRF-ir afferents arises from the CeA, suggesting that they may play an im-
portant role in differential modulation of topographically organized subpopulations of
serotonergic neurons under stress-related conditions.
17
49ABRAMS
et al.
: TOPOGRAPHY OF SEROTONERGIC SYSTEMS
FUNCTIONAL TOPOGRAPHIC ORGANIZATION OF THE DR
Behavioral Correlates of Neuronal Activity
Some of the strongest evidence for topographic organization of subpopulations of
serotonergic neurons comes from studies combining electrophysiologic data with
behavioral observations. Single-unit extracellular recording studies in cats suggested
the existence of two different types of serotonergic neurons, designated type I and
type II serotonergic neurons, based on behavioral correlates. Type I serotonergic
neurons are active during waking arousal but show decreased activity during stages
of quiet waking (QW) and slow-wave sleep (SWS) and cease firing during paradoxic
sleep (PS) or rapid eye movement sleep. Type II serotonergic neurons are highly to-
pographically organized and are found only in small numbers in bilateral columns of
cells at the caudal interface of the dorsal and median raphe nuclei (reminiscent of the
interfascicular dorsal raphe nucleus in the rat brain). Type II serotonergic neurons,
like type I neurons, are active during waking arousal and QW but remain active dur-
ing SWS and PS.
18
Due to the overwhelming preponderance of type I serotonergic
neurons, it is likely that most conclusions drawn from single-unit electrophysiology
studies are drawn from random sampling of this population of cells.
A recent study sampling a large number of presumed serotonergic neurons within
the DR using single-unit recording methods has classified them into six different
subtypes based on their electroencephalographic and behavioral correlates in cats.
19
Serotonergic neurons were classified within two large categories: (1) typical seroto-
nergic neurons (e.g., similar to type I serotonergic neurons described previously) and
(2) atypical serotonergic neurons. Among the typical and atypical serotonergic neu-
rons, subpopulations were identified that may correspond to type I and type II sero-
tonergic neurons described previously (T
ABLE
1). According to Sakai
et al.
,
19
type
I-A and type I-B serotonergic neurons are evenly distributed in the DR, discharge
regularly at a high rate during active waking and at progressively slower rates during
SWS, and cease firing during SWS or PS (type I-A) or only during PS (type I-B);
atypical type I-C serotonergic neurons are unevenly distributed in the DR (located
predominantly within the ventral DR, similar to the atypical type II serotonergic neu-
rons) and discharge regularly at a high rate during active waking but have sustained
activity during SWS and PS. Other atypical serotonergic neurons (types II-A, II-B,
and II-C) have unique topographic distributions within the DR. Type II-A neurons
are located predominantly within the dorsomedial DR and show reductions in firing
during QW and SWS; unlike typical serotonergic neurons, the level of
α
1
-adrenergic
receptor activation does not seem to be a major determinant of neuronal activity during
SWS and PS. This study of a large sample of serotonergic neurons within the DR
points toward a greater degree of functional heterogeneity of serotonergic neurons
within the DR than had previously been suspected.
Cellular Properties and Afferent Control Mechanisms
Consistent with findings that the DR consists of multiple topographically orga-
nized subpopulations of serotonergic neurons with unique behavioral correlates,
studies investigating the responses of serotonergic neurons to specific afferent sig-
nals (neurotransmitters, neuropeptides) have demonstrated that responses are depen-
dent on the topographic location of the recordings.
50 ANNALS NEW YORK ACADEMY OF SCIENCES
TABLE 1. Typical and atypical serotonergic cells of the DR in freely moving cats (as described by Rasmussen
et al
.
18
and Sakai and
Crochet
19
)
Type Firing Pattern Distribution Behavioral Correlates % Cessation Blocked By
Typical groups
I-A (similar to Type I serotonergic
neurons in Rasmussen
et al
.
18
)
Clock-like Evenly distributed Cease firing during SWS with
PGO waves and PS
40 Histamine or
phenylephrine
I-B (similar to Type I serotonergic
neurons in Rasmussen
et al
.
18
)
Clock-like Evenly distributed Cease firing during SWS only 27 Histamine or
phenylephrine
Atypical groups
I-C (similar to Type II serotonergic
neurons in Rasmussen
et al
.
18
)
Clock-like Unevenly distributed
(ventral DR)
Sustained activity during SWS
and PS
6 Histamine or
phenylephrine
II-A Nonclock-like Unevenly distributed
(dorsomedial DR)
Reduction in firing during QW
and SWS. Ceased firing
before the occurrence of PGO
waves and remained silent
during SWS with PGO waves
and PS
8 Phenylephrine has no
effect; histamine
blocks cessation of
discharge during
sleep
II-B Nonclock-like Unevenly distributed
(rostral dorsal portion
of DR, near the
oculomotor n.)
Highest rate of discharge during
SWS with suppression of
activity during waking and PS;
strongly activated during
feeding or grooming
12 Phenylephrine
II-C Nonclock-like Unevenly distributed
(ventral DR near mlf
and nucleus annularis)
Sustained activity during PS 8 Histamine
A
BBREVIATIONS
: DR, dorsal raphe nucleus; SWS, slow-wave sleep; PGO, ponto-geniculo-occiptal; PS, paradoxic sleep; QW, quiet waking.
51ABRAMS
et al.
: TOPOGRAPHY OF SEROTONERGIC SYSTEMS
Electrophysiologic studies suggest that intracerebroventricular injection of CRF
at low doses inhibits the firing rates of DR 5-HT neurons
in vivo
in a topographically
dependent manner; the majority of the cells tested (60.7%) in the ventromedial DR
(
−
7.80 mm bregma) were inhibited by CRF, whereas responses of cells in the dorso-
medial and lateral wings (ventrolateral DR) were more variable.
20,21
In vitro
exper-
iments in our laboratory have found a greater proportion of CRF-responsive neurons
in the ventral midline of the caudal DR compared with the dorsal region of the DR
at the same rostrocaudal level (–8.00 to –8.40 mm bregma).
22
Recent studies using
visualized whole-cell patch-clamp electrophysiologic techniques reveal that sero-
tonergic neurons within the dorsomedial and ventromedial DR differ with respect
to active and passive membrane characteristics,
23
further supporting distinctions
among cellular properties and afferent control mechanisms of topographically orga-
nized serotonergic neurons within this nucleus.
Heterogeneity of 5-HT neuronal firing is also demonstrated in responses to com-
pounds related to circadian fluctuations in behavioral arousal. The cessation of
serotonergic neuronal firing in serotonergic neurons of the DR observed during PS
is not the result of GABA-mediated inhibition
24
but is rather the result of lack of
facilitation resulting from the local release of norepinephrine and histamine.
19
Dif-
ferent subtypes of serotonergic DR neurons respond differentially to microdialysis
application of phenylephrine (an
α
1
-adrenergic agonist) and histamine. Typical I-A
and I-B neurons’ normal quiescence during PS is blocked by phenylephrine or his-
tamine, whereas the atypical II-A and II-C neurons’ low firing rates are unaffected
by phenylephrine but are totally (II-A) or partially (II-C) blocked by histamine
(leading to substantial tonic activity during sleep).
19
These results strongly suggest
additional heterogeneity in the behavioral correlates and afferent control mecha-
nisms of topographically organized subpopulations of serotonergic neurons within
the DR.
Behavioral Studies
Anatomic and functional heterogeneity of the DR is nowhere more evident than
in the modulation of stress-related neural circuits and stress responses. Behavioral
studies involving site-specific injections of CRF into subregions of the DR support
the hypothesis that the DR has a functional topographic organization in the rostro-
caudal plane. A series of studies has demonstrated that increased serotonergic activity
arising from the DR plays a critical role in the development of learned helplessness,
including increases in behavioral measures of anxiety and fear measured 24 to 48 h
after exposure to inescapable stress.
25–27
Further studies have shown that these be-
havioral changes are dependent on CRF actions within the DR. Microinjection of the
nonselective CRF receptor antagonist D-Phe-CRF
(12–41)
into specific sites in the
caudal DR (particularly at ~–8.30 mm bregma) blocks behavioral changes induced
by inescapable stress.
28
Microinjections of CRF into the caudal DR (but not the ros-
tral DR) are sufficient to induce learned helplessness 24 h later in the absence of any
exposure to inescapable stress,
28
consistent with the hypothesis that CRF actions on
serotonergic systems arising from the caudal portion of the DR mediate these behav-
ioral changes. This is consistent with the finding that exposure to inescapable stress
increases the expression of the protein product of the immediate-early gene
c-fos
within the middle and caudal portions of the DR but not the rostral portion. This
52 ANNALS NEW YORK ACADEMY OF SCIENCES
FIGURE 1.
Anatomic atlas of tryptophan hydroxylase (TrpOH) immunohistochemical (ir)
staining in the rat DR. Sections (30
µ
m) were obtained from an adult male Wistar rat, and
every third section was immunostained with a sheep anti-TrpOH antibody. Bregma levels (mm)
are indicated in each photograph. Scale bar represents 50
µ
m. Anatomic levels assigned
based on comparisons with a rat stereotaxic atlas.
52
evidence points toward an essential role for the caudal DR in modulating the behav-
ioral consequences of inescapable stress.
IMMEDIATE-EARLY GENE EXPRESSION STUDIES
There is a large body of data concerning the effects of stressful stimuli on the ex-
pression of immediate-early genes within the DR.
29
Investigation of the effects of
stress-related stimuli on the expression of the protein products of immediate-early
genes such as
c-fos
is an effective means of evaluating the effects of a temporally
defined stimulus on large populations of cells, with resolution of functional responses
at the single-cell level. Paradigms associated with increased anxiety or conditioned
fear,
30–41
opiate withdrawal,
42,43
and intracerebroventricular infusion of CRF or
similar anxiogenic neuropeptides
44,45
are effective at increasing immediate-early
gene expression within caudal regions of the DR. When these data are taken to-
gether with those indicating increased serotonergic neurotransmission in the DR in
response to stressful stimuli,
46,47
especially when the stressor is intense, uncontrol-
lable, or unpredictable,
48–51
they suggest a mechanism whereby anxiogenic or fear-
inducing stimuli increase serotonergic neurotransmission via actions on subsets of
serotonergic neurons within the caudal regions of the DR that give rise to a meso-
limbocortical serotonergic innervation of the forebrain.
THE NEED FOR DEFINITIVE NEUROANATOMIC MAPS
With the goal of developing better treatments for human neuropsychiatric disor-
ders in mind, it is essential that rostrocaudal levels of the DR and other raphe nuclei
be carefully defined. A survey of the literature shows widely variable definitions,
with some groups’ definitions of “caudal” regions
20,21
being almost as far forward
as others’ definitions of “rostral” ones
22
. Therefore, we propose consensus defini-
tions based on standard stereotaxic atlases of the rat
52
and mouse
53
brain and our
own atlases of rat (F
IG
. 1) and mouse brain (F
IG
. 2) immunostaining with tryptophan
hydroxylase.
According to these atlases, the “rostral” DR (regions associated with the caudal
linear nucleus, ventrally) comprises anatomic levels from –6.92 to –7.64 mm bregma
in the rat brain (–4.12 to –4.48 mm bregma in the mouse); the “middle” DR includes
anatomic levels from –7.73 to –8.45 mm bregma in the rat brain (–4.54 to –4.90 mm
bregma in the mouse), and “caudal” DR includes anatomic levels from –8.54 to
–9.26 mm in the rat brain (–4.96 to –5.32 mm bregma in the mouse). We hope that
these maps will prove useful in making meaningful comparisons among different
studies of anatomic and functional subsets of serotonergic neurons in rodent brain.
53ABRAMS
et al.
: TOPOGRAPHY OF SEROTONERGIC SYSTEMS
54 ANNALS NEW YORK ACADEMY OF SCIENCES
FIGURE 2. Anatomic atlas of TrpOH-ir staining in the mouse DR. Sections (30 µm)
were obtained from an adult male Balb/c mouse, and every second section was immuno-
stained with a sheep anti-TrpOH antibody. Bregma levels (mm) are indicated in each photo-
graph. Scale bar represents 50 µm. Anatomic levels assigned based on comparisons with a
mouse stereotaxic atlas.53
55ABRAMS
et al.
: TOPOGRAPHY OF SEROTONERGIC SYSTEMS
ACKNOWLEDGMENTS
We gratefully acknowledge the support of the BBSRC (7/S14666), the NIMH
(R01MH065702-01A1), and the Neuroendocrinology Charitable Trust. C.A. Lowry
is a Wellcome Trust Research Fellow.
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