ReviewThe dorsal raphe nucleus—From silver stainings to a role in depression
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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European Graduate School of Neuroscience (EURON).