Elsevier

Brain Research Reviews

Volume 55, Issue 2, October 2007, Pages 329-342
Brain Research Reviews

Review
The dorsal raphe nucleus—From silver stainings to a role in depression

https://doi.org/10.1016/j.brainresrev.2007.01.002Get rights and content

Abstract

Over a hundred years ago, Santiago Ramón y Cajal used a new staining method developed by Camillo Golgi to visualize, among many other structures, what we today call the dorsal raphe nucleus (DRN) of the midbrain. Over the years, the DRN has emerged as a multifunctional and multitransmitter nucleus, which modulates or influences many CNS processes. It is a phylogenetically old brain area, whose projections reach out to a large number of regions and nuclei of the CNS, particularly in the forebrain. Several DRN-related discoveries are tightly connected with important events in the history of neuroscience, for example the invention of new histological methods, the discovery of new neurotransmitter systems and the link between neurotransmitter function and mood disorders. One of the main reasons for the wide current interest in the DRN is the nucleus' involvement in depression. This involvement is particularly attributable to the main transmitter of the DRN, serotonin. Starting with a historical perspective, this essay describes the morphology, ascending projections and multitransmitter nature of the DRN, and stresses its role as a key target for depression research.

Introduction

The dorsal raphe nucleus (DRN) is a bilateral, heterogenous brainstem nucleus, located mainly in the ventral part of the periaqueductal gray matter of the midbrain. A majority of the nucleus' neurons utilize its major neurotransmitter, serotonin, but several other transmitters are also present. It comes as no surprise that the first detailed outline of what was later to be called DRN was presented by Santiago Ramón y Cajal in his famous work on the texture of the nervous system (Ramón Cajal, 1904). By skillful use of the silver chromate-impregnation method developed by Camillo Golgi, Cajal was able to reveal details about DRN morphology, which are still valid.

The DRN is an interesting area in two ways. Firstly, because it innervates a multitude of targets throughout the brain and spinal cord via its ascending and descending pathways. Secondly, because the story of DRN research nicely illustrates several major breakthroughs, paradigm shifts and the emergence of new fields of research within neuroscience. In this essay we outline the discoveries and technical advances of the past century, which have taught us what we have learned about the DRN from the times of Cajal and Golgi to the present day.

Section snippets

Cajal and Golgi

Golgi's silver chromate-impregnation method was undoubtedly of crucial importance to Cajal's success in describing the texture of the mammalian nervous system. One of the areas he studied in newborn rabbit and kitten, was the raphe area. Cajal observed that the DRN contained four types of neurons, which he described as being voluminous, fusiform, triangular and stellate. His description is in accordance with modern reports on other mammals, which also identify four morphologically distinct

The discovery of neurotransmitters

When Cajal set the stage for neuromorphological work in the early 20th century, the neuron doctrine was still heavily debated. Although opposed by Golgi, the hypothesis was supported by Cajal and by Charles Sherrington, who had coined the term “synapse” a few years earlier (in 1897). Sherrington described the synapse in 1906; the year that Cajal and Golgi received the Nobel Prize, and soon the neuron doctrine became widely accepted.

For a long time, it was debated whether the synapse is chemical

The dawn of neurochemistry

The connection between the DRN and serotonin was established when Dahlström and Fuxe (1964) described the distribution of serotonergic neurons in the rat DRN. This, and other discoveries, such as the histochemical technique for detection of cholinesterase activity introduced by Koelle and Friedenwald (1949) and modified by Lewis and Shute (1959) turned the focus of many neuroscientists towards the identification and localization of neuronal groups using specific neurotransmitters, which led to

Transmitters of the DRN

After the invention of the FIF-technique, the DRN was regarded as a more or less purely serotonergic nucleus for many years. In the mid-seventies, however, additional neurotransmitters were discovered in the DRN, and over the next two decades their number grew to more than ten (Fig. 2). Most of the discoveries were made in the rat.

DRN morphology

Over the past decades, several new methodologies have led to new discoveries about the morphology of the DRN and its projections.

The DRN is a bilateral, heterogenous brainstem nucleus, located in the ventral part of the periaqueductal gray matter of the midbrain. Its rostral end is at the level of the oculomotor nucleus and its caudal subdivision reaches well into the periventricular gray matter of the rostral pons. It has been estimated that the human DRN contains on average approximately

Functional neuroanatomy of the DRN with emphasis on depression

Major depression is one of the most common psychiatric diseases. It has an incidence of about 4% and a life-time prevalence of 12–20% in Europe (Alonso et al., 2004, Paykel et al., 2005) and, thus, a deeper understanding of its mechanisms is of high clinical importance. Dysfunction of the serotonergic system has been linked to depression, and although a dysfunctional serotonin system alone cannot explain the full pathophysiology, it is considered a key factor in depression and other mood

Summary

During the past century starting from Cajal's silver stainings, the DRN has developed from an object of purely morphological studies towards being recognized as a complex multifunctional and multitransmitter nucleus and an important target for depression research. During the next decades, understanding the interactions between the many transmitter systems of the DRN will be of crucial importance for the development of new and better treatments for depression. In addition, the DRN's involvement

Acknowledgments

K.A.M. is supported by European Union Framework 6 Integrated Project NEWMOOD Grant LSHM-CT-2004-503474 and by grants from Helsingin Sanomain 100-vuotissäätiö, Alfred Kordelinin yleinen edistys- ja sivistysrahasto, Orionin tutkimussäätiö and K. Albin Johanssons stiftelse.

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