Review
Functional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups

https://doi.org/10.1016/j.jchemneu.2011.05.008Get rights and content

Abstract

The serotonin (5HT) system of the brain is involved in many CNS functions including sensory perception, stress responses and psychological disorders such as anxiety and depression. Of the nine 5HT nuclei located in the mammalian brain, the dorsal raphe nucleus (DRN) has the most extensive forebrain connectivity and is implicated in the manifestation of stress-related psychological disturbances. Initial investigations of DRN efferent connections failed to acknowledge the rostrocaudal and mediolateral organization of the nucleus or its neurochemical heterogeneity. More recent studies have focused on the non-5HT contingent of DRN cells and have revealed an intrinsic intranuclear organization of the DRN which has specific implications for sensory signal processing and stress responses. Of particular interest are spatially segregated subsets of nitric oxide producing neurons that are activated by stressors and that have unique efferent projection fields. In this regard, both the midline and lateral wing subregions of the DRN have emerged as prominent loci for future investigation of nitric oxide function and modulation of sensory- and stressor-related signals in the DRN and coinciding terminal fields.

Highlights

ā–ŗ We review the intranuclear organization of dorsal raphe nucleus (DRN). ā–ŗ The DRN maintains an internal topography with respect to its efferent projections. ā–ŗ The lateral wing of the DRN projects exclusively to sub-cortical targets. ā–ŗ DRN lateral wing includes serotonin- and nitric oxide synthase-containing neurons. ā–ŗ 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 obsessiveā€“compulsive 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 Edingerā€“Westphal, 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 ā€œstress-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, Oā€™Hearn 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.

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