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The Dorsal Raphe Nucleus and Serotonin: Implications for Neuroplasticity Linked to Major Depression and Alzheimer's Disease

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The Dorsal Raphe Nucleus and Serotonin: Implications for Neuroplasticity Linked to Major Depression and Alzheimer's Disease G. Di Giovanni, V. Di Matteo & E. Esposito (Eds.) Progress in Brain Research, Vol. 172 ISSN 0079-6123 Copyright r 2008 Elsevier B.V. All rights reserved CHAPTER 12 The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer’s disease Kimmo A. Michelsen, Jos Prickaerts and Harry W.M. Steinbuschà Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University; European Graduate School of Neuroscience (EURON), PO Box 616, 6200 MD Maastricht, The Netherlands Abstract: The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect. Accordingly, the DRN has been strongly associated with brain dysfunction, especially mood disorders such as depression, but also Alzheimer’s disease. The DRN’s most abundant transmitter, serotonin, has received the most attention in studies on both normal brain function and disease, and lately its involvement in the regulation of neuroplasticity has been under particular scrutiny. This chapter begins with a systematic overview of what we currently know about the anatomy of the DRN and its neurons, including their ascending projections. It continues with a review of the transmitters of the DRN, followed by a discussion on the connection between the DRN and neuroplasticity. Special emphasis is put on serotonin and its central role in neuroplasticity, which is proving to be of high priority in unraveling the full picture of the cellular mechanisms and their interconnections in the etiology of major depression and Alzheimer’s disease. Keywords: dorsal raphe nucleus; serotonin; neuroplasticity; major depression; Alzheimer’s disease Introduction of various physiological functions and has been implicated in brain dysfunction, especially mood The dorsal raphe nucleus (DRN) is a bilateral, disorders such as depression. This chapter gives an heterogeneous brainstem nucleus. It is located in the overview of the current knowledge about the DRN ventral periaqueductal grey matter of the mesence- with emphasis on its neurons, transmitters and phalon, with a caudal tip reaching into the pons. The ascending projections andonitsroleindepression neurons of the DRN innervate a multitude of targets and Alzheimer’s disease (AD). throughout the brain and utilize many transmitters, of which serotonin is the most abundant and important one. The DRN is involved in the control DRN morphology The DRN is a bilateral, heterogeneous brainstem ÃCorresponding author. Tel.: +31-43-3881021; nucleus situated in the midbrain and the pons. Fax: +31-43-3671096; E-mail: [email protected] Most of its cells are located in the ventral part of DOI: 10.1016/S0079-6123(08)00912-6 233 234 the periaqueductal grey matter of the midbrain. species, the DRN can be divided into five The nucleus’ most rostral part is at the level of the subregions, namely the interfascicular, ventral oculomotor nucleus, whereas its caudal tip lies in (or ventromedial), ventrolateral (or lateral), dorsal the periventricular grey matter of the rostral pons. and caudal subregions (Baker et al., 1990). The From the 1960s to the early 1980s, the morphology DRN is also often divided along the rostrocaudal of the DRN was described in the cat (Taber et al., axis into a rostral, middle and caudal portion. 1960), man (Braak, 1970), the rabbit (Felten and All five subregions extend from the rostral to Cummings, 1979) and the rat (Steinbusch, 1981). the middle part of the nucleus, except for the Together with the caudal linear and median raphe caudal subregion, which is located in the caudal nucleus, the DRN forms the rostral or superior portion of the DRN. Abrams et al. (2004) have division of the raphe complex. The caudal or proposed detailed stereotaxic coordinates for the inferior division encompasses the raphe obscurus, boundaries of the rostral, middle and caudal raphe pallidus and raphe magnus nuclei and parts portion. Accordingly, the rat and mouse DRN of the lateral reticular formation, located in the were divided in three equally long parts along the medulla and caudal pons (Steinbusch, 1981; rostrocaudal axis. The rostral part of the rat DRN Jacobs and Azmitia, 1992). comprises levels from À6.92 to À7.64, the middle Serotonin is the major neurotransmitter of the portion levels from À7.73 to À8.45 and the caudal DRN. The morphology of the serotonergic system portion levels from À8.54 to À9.26 mm bregma. In in the DRN was first described in the rat by mouse, the proposed corresponding values are Dahlstro¨m and Fuxe (1964), using formaldehyde- À4.12 to À4.48, À4.54 to 4.90 and À4.96 to induced fluorescence (FIF) which had been deve- À5.32 mm bregma. For both species, values are loped by Falck et al. (1962) for visualization of based on stereotaxic atlases (Paxinos and Watson, monoamines. The human DRN has been estimated 1997; Paxinos and Franklin, 2001) and the to contain 235,000713,000 neurons (Baker et al., authors’ own immunostainings with tryptophan 1990), of which approximately 165,000734,000 (or hydroxylase (TPH) (Abrams et al., 2004). These 70%714%) neurons contain serotonin (Baker et coordinates deal with the rostrocaudal axis only, al., 1991). In the cat, the DRN has been estimated to but division into the five subregions is fairly easy contain 35,000 neurons, of which up to 70–80% are to make on a morphological basis. serotonergic, as demonstrated by the FIF technique (Wiklund et al., 1981; Leger and Wiklund, 1982). The rat DRN has been estimated to contain Neuron types approximately 35,000 neurons, of which about one-third are serotonergic (Descarries et al., 1982). In human, the DRN contains four main morpho- This inconsistency across cat and rat studies may be logical neuronal types (+ ¼ average mean due to methodological differences, since the rat diameter) round (+,2774 mm), ovoid (+, results were based on the measured uptake of 2774 mm; variance 20–39 mm), fusiform (+, tritiated serotonin, and only medium-sized non- 1876 mm; variance 9–37 mm) or triangular indolaminergic neurons were counted in the cat (1372 mm) cells (Baker et al., 1990). In rat, they studies. appear similar and have been described as either According to the original nomenclature small round (+,1073 mm), medium-sized fusi- by Dahlstro¨m and Fuxe, the raphe nuclei (includ- form and bipolar (+,2474 mm and 874, ing the brainstem reticular formation) are divided respectively), large fusiform (+,1872 and length into nine subdivisions, B1–B9. The subdivisions 3172 mm) and very large multipolar (+, were later renamed and slightly redefined when 3975 mm) (Steinbusch et al., 1981; Steinbusch, the nuclei were re-examined using an antibody 1984). against serotonin, and what is now considered as The four main morphologically different types of the DRN corresponds to the original subdivisions DRN neurons are differentially distributed within B6–B7, B6 being the caudal extension. In most the DRN, which seems to reflect neurochemical and 235 functional specialization. Indeed, an increasing that their tonic increase during PS compared to number of studies have supported this notion. SWS (Sakai and Crochet, 2001). Electrophysiological studies in the 1980s led to a division of rat serotonergic DRN neurons into two Distribution types, which were named Type I and Type II (or typical and atypical serotonergic neurons, respec- About two-thirds of presumed serotonergic neu- tively). Type I neurons exhibited a rhythmic firing rons were confined to classes I-A and I-B, which pattern and were called clock-like neurons, whereas were evenly distributed throughout the DRN. Type II neurons fired irregularly and were called They seemed to be identical to previously identi- non-clock-like (Nakahama et al., 1981). More fied serotonergic neurons in cat. Only 6% of recently, each type was divided into three distinct serotonergic neurons were confined to Type I-C, classes based on firing patterns during the sleep– and were mainly located in the ventral region of wake cycle as measured by single-unit recordings in the DRN. Type II-A neurons were preferentially cats. In addition, non-serotonergic DRN neurons located in the middle parts and Type II-B neurons were divided into three groups as well (Sakai and preferentially in the most rostral and dorsal parts Crochet, 2001). of the DRN. Type II-C neurons were located in the ventral portion of the DRN, close to the medial longitudinal bundle and the nucleus annul- Properties laris. Each class of Type II neurons constituted 8–12% of all serotonergic neurons. To summarize, Classes I-A and I-B displayed a regular firing the clock-like Class I neurons, which are generally pattern during waking. During waking, discharge waking-dependent, comprise almost three- rates were higher than during slow-wave-sleep fourths of serotonergic DRN neurons, whereas (SWS), whereas almost no firing occurred during the non-clock-like Class II neurons, which are paradoxical sleep (PS, also known as rapid eye generally motor-dependent, make up less than movement (REM) sleep). I-C neurons differed one-fourth (Sakai and Crochet, 2001). from I-A and -B by maintaining a fairly high level of tonic, rhythmic activity during SWS and PS, Class II-A neurons’ irregular and high discharge Projections rates correlated with motor activity and was high during active wakefulness (AW; presence of gross Efferent projections of the DRN body movements), feeding and grooming, whereas rates were significantly lower or absent during Serotonergic neurons of the DRN display a quiet wakefulness (QW; absence of gross body topographic organization along the rostrocaudal movements), SWS and PS. Class II-B neurons axis, with respect to efferent projections (Abrams displayed their highest rate of tonic activity during et al., 2004).
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