The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med Rev

Department of Pharmacology and Therapeutics, School of Medicine Clinics Hospital, Montevideo, Uruguay.
Sleep Medicine Reviews (Impact Factor: 8.51). 02/2010; 14(5):307-17. DOI: 10.1016/j.smrv.2009.11.004
Source: PubMed


Serotonergic (5-HT) cells in the rat dorsal raphe nucleus (DRN) appear in topographically organized groups. Based on cellular morphology, expression of other neurotransmitters, afferent and efferent connections and functional properties, 5-HT neurons of the DRN have been grouped into six cell clusters. The subdivisions comprise the rostral, ventral, dorsal, lateral, caudal and interfascicular parts of the DRN. In addition to 5-HT cells, neurons containing γ-aminobutyric acid (GABA), glutamate, dopamine, nitric oxide and the neuropeptides corticotropin-releasing factor, substance P, galanin, cholecystokinin, neurotensin, somatostatin, vasoactive intestinal peptide, neuropeptide Y, thyrotropin-releasing hormone, growth hormone, leu-enkephalin, met-enkephalin and gastrin have been characterized in the DRN. Moreover, numerous brain areas have neurons that project to the DRN and express monoamines (norepinephrine, histamine), amino acids (GABA, glutamate), acetylcholine or neuropeptides (orexin, melanin-concentrating hormone, corticotropin-releasing factor and substance P) that directly or indirectly, through local circuits, regulate the activity of 5-HT cells. The 5-HT cells predominate along the midline of the rostral, dorsal and ventral subdivisions of the DRN and outnumber the non-5-HT cells occurring in the raphe nucleus. The GABAergic and glutamatergic neurons are clustered mainly in the lateral and dorsal subdivisions of the DRN, respectively. The 5-HT(1A) receptor is located on the soma and the dendrites of 5-HT neurons and at postsynaptic sites (outside the DRN). It is expressed, in addition, by non-5-HT cells of the DRN. The 5-HT(1B) receptor is located at presynaptic and postsynaptic sites (outside the boundaries of the DRN). It has been described also in the ventromedial DRN where it is expressed by non-5-HT cells. The 5-HT(2A) and 5-HT(2C) receptors are located within postsynaptic structures. At the level of the DRN the 5-HT(2A) and 5-HT(2C) receptor-containing cells are predominantly GABAergic interneurons and projection neurons. Within the boundaries of the DRN the 5-HT(3) receptor is expressed by, among others, glutamatergic interneurons. 5-HT(7) receptors in the DRN are not localized to serotonergic neurons but, at least in part, to GABAergic cells and terminals. The complex structure of the DRN may have important implications for neural mechanisms underlying 5-HT modulation of wakefulness and REM sleep.

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Available from: Jaime Monti, Dec 14, 2015
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    • "Serotonergic neurons of the DR have a slow and regular firing during wakefulness, there is a decrease in their activity during NREM sleep, and an almost complete inactivation during REM sleep ( " REM-off " neurons;Monti, 2010b). A decrease in the release of serotonin in brain areas during REM sleep correlates with the electrophysiological data of DR neuronal activity (Portas and McCarley, 1994). "
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    ABSTRACT: The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.
    Full-text · Article · Dec 2015 · Frontiers in Neuroscience
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    • "We perform a genome-wide analysis of canonical and noncanonical imprinting effects in adult female mice for the arcuate nucleus of the hypothalamus (ARN), the dorsal raphe nucleus (DRN) of the midbrain, the liver (endoderm-derived), and skeletal muscle (mesoderm derived). Neuronal circuits in the ARN regulate the endocrine system, feeding, energy expenditure, and blood glucose homeostasis (Gao and Horvath, 2007; Sternson, 2013), while the DRN, a major serotonergic nucleus, influences stress and anxiety, arousal, feeding, reward, social behaviors, and pain (Challis et al., 2013; Dö len et al., 2013; Lowry et al., 2008; Michelsen et al., 2007; Monti, 2010; Wang and Nakai, 1994). By comparing imprinting in the brain to the liver and muscle, we examine the prevalence of canonical and noncanonical imprinting effects in different tissue types. "
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    ABSTRACT: Here, we describe an RNA-sequencing (RNA-seq)-based approach that accurately detects even modest maternal or paternal allele expression biases at the tissue level, which we call noncanonical genomic imprinting effects. We profile imprinting in the arcuate nucleus (ARN) and dorsal raphe nucleus of the female mouse brain as well as skeletal muscle (mesodermal) and liver (endodermal). Our study uncovers hundreds of noncanonical autosomal and X-linked imprinting effects. Noncanonical imprinting is highly tissue-specific and enriched in the ARN, but rare in the liver. These effects are reproducible across different genetic backgrounds and associated with allele-specific chromatin. Using in situ hybridization for nascent RNAs, we discover that autosomal noncanonical imprinted genes with a tissue-level allele bias exhibit allele-specific expression effects in subpopulations of neurons in the brain in vivo. We define noncanonical imprinted genes that regulate monoamine signaling and determine that these effects influence the impact of inherited mutations on offspring behavior. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell Reports
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    • "There is evidence that MCHergic fibers reach the dorsal raphe nucleus (DRN) in rats (Bittencourt et al., 1992; Lagos et al., 2011a; Yoon and Lee, 2013). The DRN contains the vast majority of the serotonergic neurons of the brain (Azmitia and Segal, 1978; Jacobs and Azmitia, 1992; Monti, 2010; Calizo et al., 2011) and it has been suggested that a dysfunction in the serotonergic neurons of the DRN underlies major depression (Underwood et al., 1999; Arango et al., 2002). "
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    ABSTRACT: Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25-100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant.
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