ReviewFunctional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups
Highlights
āŗ We review the intranuclear organization of dorsal raphe nucleus (DRN). āŗ The DRN maintains an internal topography with respect to its efferent projections. āŗ The lateral wing of the DRN projects exclusively to sub-cortical targets. āŗ DRN lateral wing includes serotonin- and nitric oxide synthase-containing neurons. āŗ Nitric oxide-producing cells in the caudal lateral wing are activated by stressors.
Introduction
In the mammalian brain, 5HT-containing neurons are found clustered within the raphe nuclei of the midbrain, pons, and medulla (Carlsson et al., 1962, Dahlstrom and Fuxe, 1964, Palkovits et al., 1974, Taber et al., 1960). As a group, these cells project to virtually all levels of the CNS (Descarries et al., 1975, Fuxe, 1965, Lidov et al., 1980, Moore et al., 1978, Ungerstedt, 1971). This broad connectivity implicates a role for 5HT over a wide range of CNS functions including sleep/arousal, learning/memory, sensory perception, motor coordination, pain regulation, and ingestive behaviors (Andersen and Dafny, 1983, Gervasoni et al., 2000, Jacobs and Azmitia, 1992, Kim and Diamond, 2002, Maier et al., 1993, McGinty and Harper, 1976, Petrov et al., 1992a, Petrov et al., 1992b, Steinbusch et al., 1981, Wang and Nakai, 1995, Waterhouse et al., 1986a, Waterhouse et al., 1986b). Dysfunction of the 5HT system is associated with the pathophysiology underlying aggressive behavior, psychostimulant drug abuse, anxiety syndromes, depressive illness, and obsessiveācompulsive disorders (Abrams et al., 2005, Blier and de Montigny, 1999, Graeff et al., 1996, Graeff et al., 1997, Molliver et al., 1990, Starr et al., 2008, Wilson et al., 1993).
The dorsal raphe nucleus (DRN), one of the major components of this system, has widely distributed efferents throughout the forebrain (Anden et al., 1965, Fuxe and Ungerstedt, 1968, Hillarp et al., 1966, Vertes, 1991). In part because of this broad connectivity, the DRN has been expressly implicated in the manifestation of a number of psychological disorders, most notably anxiety and depression (Chaouloff, 1993, Graeff et al., 1996, Underwood et al., 1999). Initial explorations of DRN topography and physiology suggested that the principal role of the nucleus was to provide for nearly simultaneous release of 5HT throughout multiple forebrain structures (Jacobs and Fornal, 1991, Jacobs and Fornal, 1999, McQuade and Sharp, 1995, Wilkinson and Jacobs, 1988). However, more recent anatomical and electrophysiological investigations have generated data which challenge the notion that the DRN is structured solely for a global mode of operation (Hajos et al., 1995, Hajos and Sharp, 1996, Kirifides et al., 2001, Lowry, 2002, Lowry et al., 2005, Varga et al., 2003, Waselus et al., 2006, Waterhouse et al., 1986a, Waterhouse et al., 1990, Waterhouse et al., 1993, Wilson and Molliver, 1991), and have demonstrated a role for the non-5HT component of the DRN in the stress response, particularly within the lateral wing subregion of the nucleus (Okere and Waterhouse, 2006a, Okere and Waterhouse, 2006b, Roche et al., 2003).
This review serves to summarize results from our laboratories and others that argue for anatomical, neurochemical, and functional order within the DRN efferent system. Investigations of DRN efferent projections, afferent inputs, and neurochemical composition clearly support the idea of a functionally segregated structure with specific connections that regulate, among other targets, sensory and stress related circuits. These defining dimensions of DRN organization point to a critical role for this nucleus during the integration of sensory information associated with stressor presentation. In light of recent studies conducted in our laboratory (Okere and Waterhouse, 2006a, Okere and Waterhouse, 2006b), we will focus on how this pattern of organization applies to the nitric oxide producing cells of the DRN and their potential contribution to the stress response.
Section snippets
Anatomy and general neurochemical topography of the DRN
The 5HT-containing neurons of the DRN correspond to the B6 and B7 groupings of Dahlstrom and Fuxe (1964). In the rat, the DRN extends for approximately 2600Ā Ī¼m, from the nucleus of EdingerāWestphal, through the pons, and into the rostral portion of the medulla at the level of the tegmental nuclei. In the coronal plane the DRN lies beneath the cerebral aqueduct and fourth ventricle and extends ventrally between the trochlear nuclei and medial longitudinal fasciculi (Fig. 1; Abrams et al., 2004,
Overview of DRN projections
Initial studies of the DRN (Anden et al., 1971; Descarries et al., 1975, Hillarp et al., 1966, Jacobs et al., 1978, Ungerstedt, 1971) identified 5HT-containing projections from this nucleus to multiple, functionally diverse regions of the CNS. These target areas include the entire cerebral cortex, thalamus, hippocampus, amygdala, cerebellum, and numerous brainstem nuclei. Although these studies utilized a variety of methods (lesions, radioactive compounds, immunohistochemistry), the origin of
Afferent regulation of DRN subregions
In order to fully appreciate the potential contribution of DRN outputs to forebrain circuits it is important to identify the sources of afferent drive to the nucleus and determine the subregional distribution of these inputs. Early studies (Aghajanian and Wang, 1977, Baraban and Aghajanian, 1981, Imai et al., 1986, Kalen et al., 1985, Pasquier et al., 1976, Sakai et al., 1977, Steinbusch et al., 1981) used combinations of anterograde and retrograde tract tracing methods to reveal inputs to the
DRN and NO contribution to the stress response
The role of stress hormones and stressors in the control of 5HT neuronal activity has received considerable attention (see Chaouloff et al., 1999). Previous electrophysiological studies on restraint stress in cat found no evidence of stressor-related alteration in DRN neuronal activity (Jacobs and Fornal, 1991, Wilkinson and Jacobs, 1988). These findings led to the conclusions that DRN-5HT cells in this species are functionally homogeneous and āstress-neutral.ā However, compelling evidence from
Concluding remarks
The 5HT cells of the DRN are distributed across the rostrocaudal, dorsoventral, and mediolateral dimensions of the nucleus according to an efferent topographic map (Abrams et al., 2004, Lowry, 2002, OāHearn and Molliver, 1984). Although the DRN in general has an extremely broad connectivity to the forebrain, the 5HT projections arising from specific subregions create selective pathways to structures that process sensory information and to limbic brain regions (Commons et al., 2003, Lowry, 2002,
Ethical approval
The authors of this work do not have any conflicts of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.
References (157)
- et al.
Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs
Neuroscience
(2005) - et al.
Intracellular recordings from serotonergic dorsal raphe neurons: pacemaker potentials and the effect of LSD
Brain Res.
(1982) - et al.
Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique
Brain Res.
(1977) - et al.
Serotonergic and non-serotonergic neurons of the dorsal raphe: reciprocal changes in firing induced by peripheral nerve stimulation
Brain Res.
(1978) - et al.
Principles for the morphological characterization of transmitter-identified nerve cell groups
J. Neurosci. Methods
(1982) - et al.
Neurochemical and anatomical identification of fast- and slow-firing neurones in the rat dorsal raphe nucleus using juxtacellular labelling methods in vivo
Neuroscience
(2003) - et al.
Mapping out of catecholamine and 5-hydroxytryptamine neurons innervating the telencephalon and diencephalon
Life Sci.
(1965) - et al.
An ascending serotonergic pain modulation pathway from the dorsal raphe nucleus to the parafascicularis nucleus of the thalamus
Brain Res.
(1983) - et al.
Quantitative and qualitative aspects on the distribution of 5-HT and its coexistence with substance P and TRH in cat ventral medullary neurons
J. Chem. Neuroanat.
(1994) - et al.
Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography
Brain Res.
(1981)
GABA-accumulating neurons in the nucleus raphe dorsalis and periaqueductal gray in the rat: a biochemical and radioautographic study
Brain Res.
Immunohistochemical evidence for the presence of gamma-aminobutyric acid and serotonin in one nerve cell. A study on the raphe nuclei of the rat using antibodies to glutamate decarboxylase and serotonin
Brain Res.
Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase
J. Neuroimmunol.
Serotonin and drug-induced therapeutic responses in major depression, obsessiveācompulsive and panic disorders
Neuropsychopharmacology
Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase
Neuron
Physiopharmacological interactions between stress hormones and central serotonergic systems
Brain Res. Brain Res. Rev.
Serotonin and stress
Neuropsychopharmacology
Locally collateralizing glutamate neurons in the dorsal raphe nucleus responsive to substance P contain vesicular glutamate transporter 3 (VGLUT3)
J. Chem. Neuroanat.
Serotonin nerve terminals in adult rat neocortex
Brain Res.
Nucleus raphe dorsalis: a morphometric Golgi study in rats of three age groups
Brain Res.
Acoustic stimulation in vivo and corticotropin-releasing factor in vitro increase tryptophan hydroxylase activity in the rat caudal dorsal raphe nucleus
Neurosci. Lett.
A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements
Brain Res.
Central monoaminergic pathways with emphasis on their relation to the so called āextrapyramidal motor systemā
Pharmacol. Ther. B
High resolution radioautographic identification of [3H]GABA labeled neurons in the rat nucleus raphe dorsalis
Neurosci. Lett.
Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons
Neuroscience
Role of 5-HT in stress, anxiety, and depression
Pharmacol. Biochem. Behav.
Dual role of 5-HT in defense and anxiety
Neurosci. Biobehav. Rev.
Evidence for a repetitive (burst) firing pattern in a sub-population of 5-hydroxytryptamine neurons in the dorsal and median raphe nuclei of the rat
Neuroscience
A 5-hydroxytryptamine lesion markedly reduces the incidence of burst-firing dorsal raphe neurones in the rat
Neurosci. Lett.
Serotonergic and nonserotonergic neurons in the dorsal raphe nucleus send collateralized projections to both the vestibular nuclei and the central amygdaloid nucleus
Neuroscience
Serotonergic modulation of the limbic system
Neurosci. Biobehav. Rev.
Differential projections of neurons within the dorsal raphe nucleus of the rat: a horseradish peroxidase (HRP) study
Brain Res.
Activity of serotonergic neurons in behaving animals
Neuropsychopharmacology
Immunohistochemical support for three putative transmitters in one neuron: coexistence of 5-hydroxytryptamine, substance P- and thyrotropin releasing hormone-like immunoreactivity in medullary neurons projecting to the spinal cord
Neuroscience
Neurotensin and the serotonergic system
Prog. Neurobiol.
Possible excitatory amino acid afferents to nucleus raphe dorsalis of the rat investigated with retrograde wheat germ agglutinin and D-[3H]aspartate tracing
Brain Res.
Distinguishing characteristics of serotonin and non-serotonin-containing cells in the dorsal raphe nucleus: electrophysiological and immunohistochemical studies
Neuroscience
Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus
Neuropsychopharmacology
Immobilization-induced stress activates neuronal nitric oxide synthase (nNOS) mRNA and protein in hypothalamicāpituitaryāadrenal axis in rats
Brain Res.
cGMP-mediated facilitation in nerve terminals by enhancement of the spike after hyperpolarization
Neuron
Reward and the serotonergic system
Neuroscience
Brainstem peptidergic neurons projecting to the medial and lateral thalamus and zona incerta in the rat
Brain Res.
Projection patterns from the amygdaloid nuclear complex to subdivisions of the dorsal raphe nucleus in the rat
Brain Res.
Glutamatergic afferent projections to the dorsal raphe nucleus of the rat
Brain Res.
Retrograde study of projections from the tuberomammillary nucleus to the dorsal raphe and the locus coeruleus in the rat
Brain Res.
Retrograde study of hypocretin-1 (orexin-A) projections to subdivisions of the dorsal raphe nucleus in the rat
Brain Res.
Organization of histamine-immunoreactive, tuberomammillary neurons projecting to the dorsal tier of the substantia nigra compacta in the rat
Brain Res.
The collateral projection from the dorsal raphe nucleus to whisker-related, trigeminal sensory and facial motor systems in the rat
Brain Res.
Morphological features and electrophysiological properties of serotonergic and non-serotonergic projection neurons in the dorsal raphe nucleus. An intracellular recording and labeling study in rat brain slices
Brain Res.
The serotonin innervation of the cerebral cortex in the ratāan immunohistochemical analysis
Neuroscience
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2020, Handbook of Behavioral NeuroscienceCitation Excerpt :Specifically, the DR distributes significantly to the several subcortical sites: the PAG, VTA, and SNc of the rostral midbrain; the perifornical/LHy, PH, and SUM nuclei of hypothalamus; the anterior, lateral, MD, midline and intralaminar, and lateral geniculate nuclei (LGN) of the thalamus; the central, lateral, basolateral, basomedial, and cortical nuclei of the amygdala; and the BST, ACC, dorsal striatum, LS, lateral preoptic area, substantia innominata (SI), magnocellular preoptic area (MgPO), VP, endopiriform nucleus (EN), and CLA of the anterior forebrain (Vertes, 1991; Morin & Meyer-Bernstein, 1999; Vertes & Linley, 2007, 2008). The main cortical targets of DR are the piriform, agranular insular, lateral agranular (frontal), MO, entorhinal (EC), and mPFC cortices (Vasudeva et al., 2011; Vertes & Linley, 2007, 2008). The primary destinations of DR fibers to the thalamus are the anteromedial (AM) anteroventral (AV) and interanteromedial (IAM) nuclei of the anterior thalamus, the MD and intermediodorsal (IMD) nuclei, the LGN complex, and the midline and intralaminar nuclei (Krout, Belzer, & Loewy, 2002; McKenna & Vertes, 2004; Morin & Meyer-Bernstein, 1999; Pechanski & Besson, 1984; Vertes, 1991).
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2020, Handbook of Behavioral NeuroscienceCitation Excerpt :Laterally to these medial cell groups lies a pair of loosely distributed 5-HT neurons forming what has elegantly been named the ālateral wingsā (B7l or DRl) (Vertes, 1991). In the B7l, 5-HT neurons are intermingled with GABA interneurons, and NOS + neurons (Simpson, Waterhouse, & Lin, 2003; Vasudeva et al., 2011). The caudalmost part of the DRN is sometimes referred to as the caudal B7 (B7c or DRc), but the frontier between B7c and B6 is unclear and these denominations are often used interchangeably.
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2019, NeuronCitation Excerpt :Additionally, DRN 5-HT neurons display heterogeneity at the level of gene expression and neurochemical phenotype (Bang et al., 2012; Hale and Lowry, 2011; Vasudeva et al., 2011). The molecular identity of individual neurons follows a topography within the DRN, as does the organization of DRN projections according to anatomical targets (Fernandez et al., 2016; Vasudeva et al., 2011). These patterns may be established during development (Calizo et al., 2011; Deneris and Gaspar, 2018), such that 5-HT neurons could be assigned to functional pathways through a combination of genetic and migratory factors early in life.