Serotonergic Systems in Sleep and Waking

Serotonergic Systems in Sleep and Waking

C H A P T E R 7 Serotonergic Systems in Sleep and Waking Stephanie B. Linley*,†, Robert P. Vertes*,† *Center for Complex Systems and Brain Sciences, ...

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C H A P T E R

7 Serotonergic Systems in Sleep and Waking Stephanie B. Linley*,†, Robert P. Vertes*,† *Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, United States †Department of Psychology, Florida Atlantic University, Boca Raton, FL, United States

I INTRODUCTION It is well established that the brainstem contains discrete groups of serotonin-containing (5-hydroxytryptamine, 5-HT) neurons, extending from the caudal medulla to the rostral midbrain. These midline “raphe” nuclei, originally identified as B1-B9 by Dahlstr€ om and Fuxe (1964), can be further divided into a caudal group (raphe magnus, raphe pallidus, and raphe obscurus) with projections mainly descending to the lower brainstem and spinal cord and a rostral group, primarily consisting of the dorsal raphe (DR) and median raphe (MR) nuclei, which distribute extensively to the forebrain (Vertes & Linley, 2007, 2008). In addition, various types of serotonin receptors are distributed heterogeneously throughout the brain—with differential actions on target sites (Nichols & Nichols, 2008). This places serotonin as a key modulator of several functions, prominently including sleepwake states as well as affect, cognition/memory, and thermoregulation (Datta & Maclean, 2007; Jacobs & Azmitia, 1992; Štrac, Pivac, & M€ uck-Šeler, 2016; Ursin, 2002; Vertes & Linley, 2007, 2008). In this chapter, we will (1) provide a brief overview of the anatomy and organization of the dorsal and median raphe nuclei; (2) discuss the role of the DR and MR in sleep and wakefulness; and (3) and review the involvement of 5-HT and 5-HT receptors in the modulation of vigilance states, including non-REM and REM sleep.

II ANATOMY OF 5-HT NEURONS OF THE DORSAL AND MEDIAN RAPHE NUCLEI As is well recognized, the dorsal and median raphe nuclei are densely populated with serotonergic neurons—

Handbook of Sleep Research, Volume 30 ISSN: 1569-7339 https://doi.org/10.1016/B978-0-12-813743-7.00007-4

DR more so than MR. At the midbrain, 5-HT cells of DR are mainly concentrated along the midline, whereas further caudally, they not only are found on the midline but also extend laterally, forming the “lateral wings” of DR (Fig. 7.1). Serotonergic cells of DR are typically large (30–40 μm), fusiform in shape, stain darkly for 5-HT, and contain about 4–5 primary dendrites radiating from the cell body. By comparison, the MR contains considerably fewer 5-HT neurons, dispersed fairly evenly throughout MR (Fig. 7.1). Those located dorsally in MR are predominantly small (10–12 μm), oval, and stain lightly for 5-HT, whereas 5-HT neurons of the ventral MR are medium-sized (15–22 μm) and either oval- or spindle-shaped. The dendrites of the oval cells are short (10–20 μm) and coarse, while those of the spindle-shaped neurons are generally long (40–150 μm). Surprisingly, despite the interest in 5-HT systems, relatively few studies have quantified numbers of 5-HT neurons in the raphe nuclei. Early reports estimated the number of 5-HT cells in MR at 1100 cells and in DR at 11,500 cells (Descarries, Watkins, Garcia, & Beaudet, 1982). We reported the following values for the rat: 5-HT cells in DR ¼ 15,191, in MR ¼ 4114, in the supralemniscal nucleus (B9) ¼ 4571, and in the pontomesencephalic reticular formation (RF) ¼ 1948 (Vertes & Crane, 1997). As is evident, the DR is the major 5-HT-containing cell group of the brain. Serotonergic neurons are heterogeneous in genetic makeup, have specific morphological and physiological properties, and coexpress transmitter/modulator substances (Gaspar & Lillesaar, 2012). Regarding the latter, DR neurons coexpress several peptides, including enkephalin, dynorphin, substance P, galanin, somatostatin, nitric oxide, neuropeptide Y, angiotensin, cholecystokinin, neurotensin, and corticotropin-releasing factor (Baker, Halliday, Hornung, Geffen, & Cotton, 1991; Bj€ orklund & H€ okfelt, 1985; Commons, Connolley, & Valentino, 2003; Fu et al., 2010; H€ okfelt, Elde, Johansson, Terenius, &

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FIG. 7.1 (A) Light field photomicrograph of a transverse section through the upper brainstem showing serotonin (5-HT)-immunostained cells in the dorsal raphe nucleus (DR) (including the lateral wings of DR), the median raphe nucleus (MR), and the supralemniscal nucleus (SLN/B9). Higher magnification photomicrographs of DR (B), MR (C), and SLN (D) showing 5-HT-labeled cells within each nucleus. Abbreviations: AQ, cerebral aqueduct; RPO, nucleus pontis oralis. Scale bar for (A) ¼ 500 μm and for (B), (C), and (D) ¼ 250 μm.

Stein, 1977; Lowry et al., 2008; Melander et al., 1986; Rodrigo et al., 1994; Simpson, Waterhouse, & Lin, 2003). In addition, DR contains a relatively significant percentage of nonserotonergic cells, most notably GABAergic, glutamatergic (GLUT), and dopaminergic (DA) neurons. DA cells are mainly located rostrally in DR (Descarries, Berthelet, Garcia, & Beaudet, 1986; Trulson, Cannon, & Raese, 1985), while GLUT neurons are found throughout the DR—with relatively large numbers coexpressing 5-HT (Commons, 2009; Fu et al., 2010; Gras et al., 2002; Herzog et al., 2004; Jackson, Bland, & Antle, 2009; SoizaReilly & Commons, 2011; Szőnyi et al., 2016). By contrast, GABAergic neurons of DR essentially comprise a separate population, as few coexpress 5-HT (Calizo et al., 2011; Day et al., 2004; Fu et al., 2010). Serotonergic neurons exhibit a rather diverse electrophysiological profile. The largest percentage (and best characterized) of 5-HT cells displays a slow tonic rate of firing (3 Hz), with characteristic patterns of activity across sleep-waking states. Specifically, they fire at highest rates in waking, slow in non-rapid eye movement (NREM) sleep, and are virtually silent in REM sleep. A smaller subset of 5-HT DR neurons, however, discharge “atypically” in waking, that is, fire at rates of >10 Hz (Kocsis, Varga, Dahan, & Sik, 2006; Urbain, Creamer, & Debonnel, 2006).

III DR PROJECTIONS TO THE FOREBRAIN—WITH IMPLICATIONS FOR SLEEP/WAKE STATES It is well established that DR fibers distribute widely throughout the neuraxis, providing a large percentage of the serotonergic innervation of the forebrain (Halliday, Harding, & Paxinos, 1995; Harding, Paxinos, & Halliday, 2004; Jacobs & Azmitia, 1992). With some differences among reports, several early studies showed that DR strongly targets several forebrain structures including the midline and intralaminar nuclei of the thalamus, the hypothalamus, subnuclei of the amygdala, the dorsal and ventral striatum, the septum, and much of the cortical mantle (Descarries et al., 1982; Moore, Halaris, & Jones, 1978). Our more recent examination of DR projections (Vertes, 1991) confirmed previous findings and extended them to show prominent DR projections to the supramammillary nucleus (SUM), basomedial/basolateral nuclei of the amygdala, bed nucleus of the stria terminalis (BNST), median (MnPO) and lateral preoptic (LPO) areas, and the claustrum (subcortically) and to the medial orbital (MO), infralimbic (IL), prelimbic (PL), anterior cingulate (AC), agranular insular (AIg), and entorhinal cortices (cortically) (Vertes, 1991).

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III DR PROJECTIONS TO THE FOREBRAIN—WITH IMPLICATIONS FOR SLEEP/WAKE STATES

A DR Projections to the Basal Forebrain DR fibers distribute widely over the basal forebrain (BF) (Morin & Meyer-Bernstein, 1999; Vertes, 1988, 1991), particularly to regions implicated in sleep/wake control such as (1) the acetylcholine-containing (ACh) groups of the BF (Luiten, Gaykema, Traber, & Spencer, 1987; Rye, Wainer, Mesulam, Mufson, & Saper, 1984; Woolf, Eckenstein, & Butcher, 1984) involved in modulating cortical EEG activity across sleep-waking states (Jones, 2004; Sarter & Bruno, 1999; Sarter, Hasselmo, Bruno, & Givens, 2005; Woolf, 1991; Zaborszky, 2002) and (2) neighboring cell groups responsible for the initiation and maintenance of NREM sleep, primarily the VLPO and MnPO. Serotoninergic fibers, mainly from DR, distribute densely to VLPO (Chou et al., 2002; Datta & Maclean, 2007; Saper, Cano, & Scammell, 2005; Saper, Scammell, & Lu, 2005; Zardetto-Smith & Johnson, 1995), and as will be discussed, GABAergic cells of the VLPO project, in turn, to DR to suppress activity in the transition from waking to NREM sleep (Saper, Cano, et al., 2005).

B DR Projections to the Diencephalon: Thalamus We recently examined the serotonergic innervation of the thalamus in the rat and found that 5-HT fibers distribute densely (and selectively) to the “limbic thalamus”—as well

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as to parts of the visual thalamus (Vertes, Linley, & Hoover, 2010). The designation “limbic thalamus” refers to thalamic nuclei interconnected extensively with limbic subcortical and cortical structures (Bentivoglio, Balercia, & Kruger, 1991; Van der Werf, Witter, & Groenewegen, 2002; Vertes, Hoover, Do Valle, Sherman, & Rodriguez, 2006; Vertes, Linley, & Hoover, 2015). The main thalamic targets of 5-HT fibers were the anteroventral and anteromedial nuclei of anterior thalamus; the central lateral, paracentral, and central medial nuclei of the intralaminar thalamus; and the paratenial, paraventricular, rhomboid, and reuniens (RE) nuclei of the midline thalamus (Fig. 7.2). Serotonergic fibers to the limbic thalamus primarily originate from the DR (Krout, Belzer, & Loewy, 2002; McKenna & Vertes, 2004; Meyer-Bernstein & Morin, 1996; Morin & MeyerBernstein, 1999; Peschanski & Besson, 1984; Sikes & Vogt, 1987; Vertes, 1991; Vertes et al., 2010, 2015; Villar, Vitale, H€ okfelt, & Verhofstad, 1988). Of the midline nuclei, RE of the ventral midline thalamus is particularly noteworthy, as it is reciprocally connected with the hippocampal formation (HF) and the medial prefrontal cortex (mPFC) (Hoover & Vertes, 2007, 2012; McKenna & Vertes, 2004; Vertes, 2002, 2006; Vertes et al., 2015), and receives widespread input from arousal-/affect-related sites (Bayer et al., 2002; Huang, Ghosh, & van den Pol, 2006; McKenna & Vertes, 2004; Vertes et al., 2015). This led to the proposal (Van der Werf et al., 2002), subsequently confirmed, that RE serves a critical role in arousal

FIG. 7.2 Light field photomicrograph of a transverse section through the diencephalon showing the pattern of distribution of serotonin transporter protein (SERT)-immunopositive fibers at midlevels of the thalamus. Note the dense plexus of serotoninergic fibers dorsoventrally throughout the midline and within the paraventricular (PV), central medial (CM), rhomboid (RH), and reuniens (RE) nuclei. By comparison, the reticular nucleus (RT) of thalamus was lightly to moderately labeled. Abbreviations: CL, central lateral nucleus of thalamus; IMD, intermediodorsal nucleus of thalamus; LD, laterodorsal nucleus of thalamus; LH, lateral habenula; MD, mediodorsal nucleus of thalamus; MH, medial habenula; PCN, paracentral nucleus of thalamus; sm, stria medullaris; SMT, submedial thalamus; VAL, ventral anterior lateral nucleus of thalamus; VB, ventral basal nucleus of thalamus; VM, ventral medial nucleus of thalamus; ZI, zona incerta. Scale bar ¼ 400 μm. Figure adapted from Vertes, R. P., Linley, S. B., & Hoover, W. B. (2010). Pattern of distribution of serotonergic fibers to the thalamus of the rat. Brain Structure and Function, 215, 1–28.

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and attention—in part involving DR actions on RE (Cassel et al., 2013; Schiff, 2008; Van der Werf et al., 2002; Vertes et al., 2015). Serotonergic fibers also distribute moderately to the reticular nucleus (RT) of the thalamus (Vertes, 1991; Vertes et al., 2010)—mainly arising from DR and the supralemniscal nucleus (B9) (Rodríguez, Noristani, Hoover, Linley, & Vertes, 2011). As will be discussed, serotonin suppresses spindle activity in NREM, an effect putatively involving DR-RT projections.

C DR Projections to the Diencephalon: Hypothalamus DR projections to the hypothalamus are rather modest (Muraki et al., 2004; Van de Kar & Lorens, 1979; Vertes, 1991; Yoshida, McCormack, España, Crocker, & Scammell, 2006), with denser projections to regions involved in arousal/wakefulness, particularly the orexin-containing (ORX) cells of the perifornical/lateral hypothalamus (LHy) (Chowdhury & Yamanaka, 2016; Sakurai et al., 2005), where 5-HT produces (via multiple receptor types) predominantly inhibitory but also some excitatory effects. For instance, it has been shown that serotonin, via 5-HT1A receptors, hyperpolarizes ORX neurons to dampen their activity during wakefulness (Chowdhury & Yamanaka, 2016; Muraki et al., 2004; Sakurai et al., 2005; Sinton, 2008; Yamanaka, Muraki, Tsujino, Goto, & Sakurai, 2003). Nonetheless, the recent demonstration of various types of 5-HT receptors (5-HT1B, 5-HT2A, 5-HT2C, and 5-HT3) on ORX cells indicates a more complex 5-HT effect than previously described (Jalewa et al., 2014). The DR also distributes to other types of cells of the LHy, commonly to GABAergic neurons, which contact and hence suppress ORX cells (Chowdhury & Yamanaka, 2016; Jalewa et al., 2014). In this regard, Chowdhury and Yamanaka (2016) showed that optogenetically activating 5-HT axon terminals on GABAergic LHy neurons hyperpolarized ORX cells of the LHy. As the DR affects states of vigilance via input to diencephalic structures, there are prominent return projections from the diencephalon to DR—much heavier from the hypothalamus than from the thalamus. Hypothalamo-DR projections originate almost entirely from regions involved in the modulation of sleep/wake states or circadian rhythms: the LHy, the tuberomammillary nucleus (TMN), and the dorsomedial nucleus (DMH) of the hypothalamus (Aghajanian & Wang, 1977; Kalen, Karlson, & Wiklund, 1985; Lee, Kim, Valentino, & Waterhouse, 2003; Lee, Kim, & Waterhouse, 2005; Lee, Lee, & Waterhouse, 2005; Peschanski & Besson, 1984; Peyron et al., 1998; Peyron, Petit, Rampon, Jouvet, & Luppi, 1997; Saper, Scammell, et al., 2005; Saper, Swanson, & Cowan, 1979; Thompson, Canteras, & Swanson, 1996). For example, the DR receives significant input from ORX cells of the LHy (Fig. 7.3; Lee, Park, Song, & Waterhouse, 2005; Peschanski & Besson,

FIG. 7.3 Light field photomicrograph of a transverse section through the upper brainstem showing a dense concentration of orexin-A-labeled fibers throughout the dorsal raphe (DR); surrounding regions of the periaqueductal gray, including the ventrolateral periaqueductal gray (vlPAG); and the median raphe nucleus (MR). Abbreviations: AQ, cerebral aqueduct. Scale bar ¼ 500 μm.

1984; Peyron et al., 1998; Wang et al., 2005). Orexin excites serotonergic DR cells, presumably to complement orexin’s role in arousal/wakefulness (Brown, Sergeeva, Eriksson, & Haas, 2001; Liu, Van Den Pol, & Aghajanian, 2002; Takahashi et al., 2005; Tao et al., 2006; Tsunematsu et al., 2011). It should be noted, however, that ORX cells also project to GABAergic neurons of the DR to suppress DR activity through an inhibitory feedforward mechanism (Liu et al., 2002). In effect, whereas ORX directly excites DR cells during waking, indirect effects mediated by GABAergic interneurons may dampen the strong depolarizing actions of ORX on serotonergic DR cells to maintain their slow tonic rate of firing. As Sinton (2008) points out, “the GABAergic tone in the raphe is important for the regulation of the spontaneous discharge rate and release of 5-HT, including the change associated with vigilance state.” While an early report by Peyron et al. (1998) described modest TMN projections to DR, a more recent study demonstrated relatively pronounced TMN-DR projections to virtually all subdivisions of DR (Lee, Lee, et al., 2005). Although a significant percentage of TMN cells

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III DR PROJECTIONS TO THE FOREBRAIN—WITH IMPLICATIONS FOR SLEEP/WAKE STATES

projecting to DR are histaminergic, a sizeable number are GABAergic cells (Gervasoni et al., 2000; Lee, Lee, et al., 2005). Melanin-concentrating hormone (MCH) neurons of the LHy are also a rather prominent source of input to DR—as well as to other “arousal-associated” nuclei of the brainstem (Torterolo, Lagos, Sampogna, & Chase, 2008; Torterolo et al., 2015; Yoon & Lee, 2013). While MCH neurons serve a well-recognized role in feeding and energy homeostasis, this cell group has received renewed interest in the modulation of vigilance states due to its involvement in REM sleep control (for review, see Monti, Torterolo, & Lagos, 2013; Nahon, 2006). For instance, infusions of MCH into the DR significantly enhance REM sleep, modestly increase slow-wave sleep (SWS), and reduce time spent in waking (Lagos, Torterolo, Jantos, Chase, & Monti, 2009). By comparison, decreasing the levels of MCH, via delivery of MCH antibodies to DR, suppressed REM sleep and increased waking time (Lagos, Torterolo, Jantos, & Monti, 2011). As will be discussed, 5-HT DR neurons (and other monoaminergic

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cells) normally act to suppress REM sleep, whereas their inhibition is permissive to REM sleep (or REM-off neurons). The REM-enhancing effect of MCH likely involves an inhibition of serotonergic DR neurons (see below). The DMH represents an additional “hub” in the homeostatic regulation of various functions, including circadian influences on sleep, feeding, temperature, and locomotor activity (Bi, Kim, & Zheng, 2012; Fuller, Gooley, & Saper, 2006; Saper, Scammell, et al., 2005). The DMH distributes substantially to the DR and may be an important link in the circadian control of sleepwaking states (Deurveilher & Semba, 2005; Fuller et al., 2006; Peyron et al., 1998; Saper, Scammell, et al., 2005).

D DR Projections to the Cortex Regions of the “limbic cortex” are the main targets of cortical projections from DR. These include the medial orbital, agranular insular, piriform, mPFC (AC, PL, IL), and entorhinal cortices (Fig. 7.4) (Hoover & Vertes,

FIG. 7.4 High-magnification photomicrographs showing patterns of distribution of 5-HT-labeled fibers within the infralimbic (IL) cortex (A), within caudal (A) and rostral (B) levels of the prelimbic (PL) cortex, and within the dorsal (ACd) and ventral (ACv) anterior cingulate cortex (C). Note the dense collections and laminar organization of 5-HT fibers across the various components of the medial prefrontal cortex. Scale bar for (A) ¼ 250 μm, for (B) ¼ 175 μm, and for (C) ¼ 150 μm. Adapted from Linley, S. B., Hoover, W. B., & Vertes, R. P. (2013). Pattern of distribution of serotonergic fibers to the orbitomedial and insular cortex in the rat. Journal of Chemical Neuroanatomy, 48, 29–45. PART B. REGULATION OF WAKING AND SLEEPING

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2007; Linley, Hoover, & Vertes, 2013; O’Hearn & Molliver, 1984; Vertes, 1991). The DR distributes much less heavily to association, somatosensory, and special sensory regions of the cortex (Vertes, 1991). This parallels the virtual absence of serotonergic projections to somatomotor regions of the thalamus (Vertes et al., 2010). In line with DR input to limbic cortices, return cortical projections to DR primarily originate from these same cortical sites, that is, the orbitomedial prefrontal and insular cortices (Gabbott, Warner, Jays, Salway, & Busby, 2005; Hoover & Vertes, 2007, 2011; Jasmin, Granato, & Ohara, 2004; Peyron et al., 1997; Sesack, Deutch, Roth, & Bunney, 1989; Vertes, 2004). Notably, the prefrontal cortex (PFC) is a principal source of glutamatergic input to DR (Lee et al., 2003). The pronounced reciprocal DR-PFC projections could be the substrate for the modulatory effects of environmental stimuli/events on states of sleep (Hensler, 2006).

E DR Projections to the Brainstem The DR sends fibers widely throughout the brainstem, mainly to brainstem nuclei implicated in sleep-wake control (Brown, Basheer, McKenna, Strecker, & McCarley, 2012; Vertes & Kocsis, 1994), including the midbrain reticular formation (RF), the medial and lateral parabrachial nuclei, nucleus reticularis pontis oralis (RPO) and reticularis pontis caudalis (RPC), the AChcontaining laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei, MR, the locus coeruleus (LC), and nucleus gigantocellularis-pars ventralis (Brown et al., 2012; Datta & Maclean, 2007; Koyama & Kayama, 1993; Semba, 1993; Steininger, Rye, & Wainer, 1992; Steininger, Wainer, Blakely, & Rye, 1997; Vertes, 1984, 1990; Vertes & Kocsis, 1994). There are significant interconnections between DR and the LC and between DR and the LDT/PPT. It appears that DR projections to LC are considerably more pronounced than LC-DR projections (Jones & Moore, 1977; Kim, Lee, Lee, & Waterhouse, 2004; Lee et al., 2003; Peyron, Luppi, Fort, Rampon, & Jouvet, 1996; Steininger et al., 1992; Vertes & Kocsis, 1994). As will be discussed, 5-HT DR projections to LDT/PPT serve a permissive role in ponto-geniculo-occipital (PGO) spike generation, that is, when active, DR cells suppress PGO spikes and, when silent, release them (Brown et al., 2012; Datta & Maclean, 2007).

IV MEDIAN RAPHE (MR) PROJECTIONS TO THE FOREBRAIN Similar to DR, the median raphe (MR) nucleus distributes widely throughout the forebrain. There are, however, distinct differences in the ascending projections of

MR and DR; in fact, with the exception of a few forebrain sites, there is no overlap in the two sets of projections. Specifically, the DR is largely a “lateral system” distributing to the LHy/lateral basal forebrain, the amygdala, the dorsal and ventral striatum, and regions of the cortex (see above). By contrast, the MR is best viewed as a medial system, with output mainly directed to medial/midline structures, such as the interpeduncular nucleus, mammillary body, midline and intralaminar thalamus, lateral habenula, medial basal forebrain, medial septum, and hippocampus (Azmitia & Segal, 1978; Bobillier, Seguin, Degueurce, Lewis, & Pujol, 1979; Vertes, Fortin, & Crane, 1999; Vertes & Martin, 1988). Overall, MR projections to the cortex are light and essentially restricted to the perirhinal, entorhinal, and PFC cortices. Although the MR and DR project to the hippocampus, MR projections considerably exceed those of DR. MR fibers reach all parts of the dorsal and ventral HF, terminating densely in the outer molecular layer (stratum lacunosum moleculare) of CA1 and CA3 of Ammon’s horn and within the inner molecular and granule cell layers of the dentate gyrus (DG). Approximately, 8%–12% of MR cells send collateral projections to the septum and hippocampus (McKenna & Vertes, 2001), suggesting a simultaneous influence on both structures. As discussed below, the MR serves a well-recognized role in the modulation of the EEG activity of HF; in effect, the MR “desynchronizes” the hippocampal EEG or blocks the theta rhythm (Vertes, 2010; Vertes, Hoover, & Viana Di Prisco, 2004). The theta rhythm is controlled by an ascending brainstem-diencephalo-septohippocampal system (Vertes & Kocsis, 1997) involving the nucleus pontis oralis (at its origin), the supramammillary nucleus (SUM), the medial septum, and the HF. The MR projects to each of these sites and, as such, could disrupt theta (producing asynchronous HF activity) by suppressing the activity of any (or all) of these structures. The MR is the major source of serotonergic input to suprachiasmatic nucleus (SCN) in the regulation of circadian rhythms (Deurveilher & Semba, 2005; HaySchmidt, Vrang, Larsen, & Mikkelsen, 2003; Morin & Meyer-Bernstein, 1999; Vertes et al., 1999; Vertes, Linley, Hoover, & Hughes, 2007; Yamakawa & Antle, 2010) (Fig. 7.5). Although the SCN provides no direct feedback to the MR (or to DR), the SCN communicates with the DMH and the subparaventricular nucleus of the hypothalamus, which target MR (Behzadi, Kalen, Parvopassu, & Wiklund, 1990; Deurveilher & Semba, 2005; Fuller et al., 2006; Marcinkiewicz, Morcos, & Chretien, 1989; Peschanski & Besson, 1984; Saper, Scammell, et al., 2005). This circuitry is important for the circadian control of vigilance states. Finally, similar to DR, the MR receives relatively pronounced input from several structures implicated in sleep-wake control, including the VLPO, the

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the densest sources of afferent projections to MR (Marcinkiewicz et al., 1989). MR (and DR) communication with LC, LDT, PPT, and the parabrachial nuclei is critical for the modulation of the state of REM sleep and REMassociated events (Brown et al., 2012; Datta & Maclean, 2007; Vertes, 1990) (see below).

V ROLE OF SEROTONIN IN AROUSAL AND VIGILANCE STATES

FIG. 7.5 Light field photomicrographs through the anterior hypothalamus showing 5-HT-labeled fibers in the suprachiasmatic nucleus (SCN). (A) No loss of 5-HT fibers in SCN in a rat treated with parachloroamphetamine (PCA, 10 mg/kg i.p.), which reportedly abolishes thin 5-HT fibers with small varicosities mainly originating from the dorsal raphe (DR) nucleus. (B) By contrast, an injection of 5,7dihydroxytryptamine (5,7-DHT) into the median raphe nucleus (MR), which selectively destroys 5-HT neurons, produced a complete loss of 5-HT fibers in the SCN. This indicates that serotonergic fibers innervating the SCN predominantly, if not exclusively, originate from the MR and not the DR. Abbreviations: LHy, lateral hypothalamus; MnPO, median preoptic nucleus; ocx, optic chiasm. Scale bar for (A) and (B) ¼ 500 μm.

perifornical/LHy, and the DMH (Behzadi et al., 1990; Pollak Dorocic et al., 2014; Lu et al., 2002; Marcinkiewicz et al., 1989; Peschanski & Besson, 1984; Saper et al., 1979; Sherin, Elmquist, Torrealba, & Saper, 1998; Steininger, Gong, McGinty, & Szymusiak, 2001). ORX fibers distribute throughout MR (Fig. 7.3) suggesting that a significant percentage of LHy projections to MR are orexinergic (Peyron et al., 1998; Tao et al., 2006). MCH fibers, however, also project quite heavily to MR (Lopez-Hill, Pascovich, Urbanavicius, Torterolo, & Scorza, 2013).

A MR Projections to the Brainstem The main brainstem targets of MR fibers are the LDT/PPT, pontomesencephalic central gray, LC, nucleus incertus, and other raphe nuclei including DR (Beitz, Clements, Mullett, & Ecklund, 1986; Olucha-Bordonau et al., 2003; Semba, 1993; Steininger et al., 1992; Tischler & Morin, 2003; Vertes et al., 1999). MR also distributes moderately to the brainstem RF—the medulla through the midbrain. Particularly noteworthy for sleepwake control is the demonstration that MR is strongly and reciprocally connected with LDT and LC (Behzadi et al., 1990; Jones & Moore, 1977; Marcinkiewicz et al., 1989; Satoh & Fibiger, 1986). In fact, the LDT is one of

Serotonin remains perhaps one of the most provocative of the neuropeptides, neurohormones, and transmitter substances associated with arousal and sleep. Over at least the last 50 years of research, it has been variously postulated that serotonin promotes sleep or alternatively facilitates arousal. While more recently, serotonin has been linked to the control of waking, 5-HT effects differ from those of other arousal-related monoaminergic groups in that 5-HT exerts differential (or even opposing) actions on sleep/wake structures, mediated by various 5-HT receptor subtypes. As such, serotonin serves a unique role in the control of wake, NREM, and REM sleep states.

A Historical Perspectives on the Role of Serotonin in Sleep One of the most common myths across dining room tables and living room couches every November (in the United States) is the fatigue and malaise that set in after consuming a large Thanksgiving “turkey” dinner— generally attributed to the consumption of large amounts of tryptophan, the amino acid precursor of 5-HT. This myth may have, in part, arisen from early studies of Jouvet and colleagues (and other labs), suggesting that serotonin was a trigger for sleep. This view was supported by early pharmacological studies, which found that 5-HT or its agonists, administered peripherally or intracerebroventricularly (ICV), produced long trains of cortical EEG synchronization and sleep in animals (for review, Jouvet, 1969, 1999; Ursin, 2002). Specifically, infusions of 5-HT initially produced arousal, followed by a period of cortical slow oscillation characteristic of SWS (Brodie, Pletscher, & Shore, 1955; Koella, 1969; Koella & Czicman, 1966). In addition, the application of monoamine oxidase inhibitors, in animal and human subjects, dramatically suppressed REM sleep (see below), thereby substituting SWS for decreases in REM sleep (Cohen et al., 1982; Jouvet, 1969, 1999; Kupfer & Bowers, 1972; Monti, 1989). Finally, Jouvet and colleagues reported that raphe lesions produced marked insomnia in cats, which persisted for extended periods of time (Jouvet, 1969; Pujol, Buguet, Froment, Jones, & Jouvet, 1971).

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Supporting these initial findings, it was subsequently shown that parachlorophenylalanine (PCPA), which inhibits 5-HT biosynthesis, depleting stores of 5-HT, also gave rise to insomnia associated with significant decreases in both SWS and REM sleep (Koe & Weissman, 1966; Mouret, Bobillier, & Jouvet, 1968). Moreover, the PCPA-induced insomnia could be attenuated by the administration of the serotonin precursor, 5hydroxytryptophan (5-HTP) (Koella, Feldstein, & Czicman, 1968; Pujol et al., 1971). Further, the administration of the amino acid precursor, L-tryptophan, before sleep reduced sleep onset latency in humans and increased cortical slow-wave activity during wakefulness (Hartmann, 1976; Hartmann & Cravens, 1974; Hartmann, Lindsley, & Spinweber, 1983; Spinweber, Ursin, Hilbert, & Hildebrand, 1983). Finally, L-tryptophan produced subjective feelings of sleepiness, lethargy, and a loss of vigor in human subjects (Hartmann, 1976, 1982). The foregoing, then, supported Jouvet’s original theory that serotonin promotes sleep—and that dopamine and norepinephrine enhance arousal/wakefulness (Jouvet, 1969). As will be discussed below, recent findings indicate a much greater involvement of serotonin/raphe nuclei in waking than in sleep.

B Electrophysiological Properties of Raphe Neurons Across the Sleep Wake Cycle 1 Dorsal Raphe Nucleus In an initial study describing the discharge properties of 5-HT DR neurons across sleep-wake states in freely behaving cats, McGinty and Harper (1976) reported that serotonergic DR neurons displayed the following characteristics: (1) fired at slow (0.5–5.0 Hz) regular rates in waking; (2) showed an approximate 46% reduction in discharge rate in SWS from waking; and (3) exhibited a further reduction in firing rate (about 92%) in REM from waking, such that the cells essentially ceased firing during REM sleep (McGinty & Harper, 1976). Shortly thereafter, a series of studies by Jacobs and colleagues (Fornal, Auerbach, & Jacobs, 1985; Heym, Steinfels, & Jacobs, 1982; Rasmussen, Heym, & Jacobs, 1984; Trulson & Jacobs, 1979; Trulson, Jacobs, & Morrison, 1981), analyzing the properties of DR neurons across sleep-wake states in cats, confirmed the initial findings that 5-HT DR cells discharge at a rate of about 3 Hz in quiet waking, with reductions in the rate of 34%–68% in SWS and 98% in REM sleep (Trulson & Jacobs, 1979). They also described an increase in DR activity during periods of active waking (with movement) and to the presentation of sensory stimuli (Trulson & Jacobs, 1979). Following these initial reports, an extensive body of research further defined the physiological and behavioral correlates of 5-HT DR cells under various conditions

across species. Recent findings have confirmed that most serotonergic DR cells exhibit a slow tonic “pacemaker” rate of firing (3 Hz) during waking, with progressively decreasing rates from SWS to REM sleep (Aghajanian & Vandermaelen, 1982; Beck, Pan, Akanwa, & Kirby, 2004; Burlhis & Aghajanian, 1987; Gervasoni et al., 2000; Guzmán-Marín et al., 2000; Kirby, Pernar, Valentino, & Beck, 2003; Sakai, 2011; Sakai & Crochet, 2001; Shima, Nakahama, & Yamamoto, 1986; Wu et al., 2004). Some reports, however, recording from 5-HT and non-5-HT DR neurons, have identified a more heterogeneous population of DR cells. For instance, Sakai and Crochet (2001) reported that 5-HT DR neurons generally shared similar firing properties but with notable differences in discharge rates (and sleep-wake profiles), depending on cell locations in the DR. For instance, cells in the central core of DR were found to be “typical” 5-HT neurons, whereas select populations (of putative 5-HT neurons) of the dorsal and rostral DR discharged “atypically,” exhibiting increased activity in SWS and, in some cases, even in REM sleep (Sakai & Crochet, 2001). In a similar manner, Urbain et al. (2006), recording from rats, reported that the majority (83%) of 5-HT DR displayed the characteristic slow tonic rate of firing in waking, with predictable decreases in SWS and REM sleep. However, interestingly, they observed a separate population of cells with higher mean firing rates in SWS and REM sleep than in waking—or the “mirror image” of typical 5-HT neurons (Urbain et al., 2006). They concluded that these cells were very likely GABAergic neurons that served to suppress (or silence) 5-HT DR cells in SWS and REM sleep (Levine & Jacobs, 1992; Nitz & Siegel, 1997; Urbain et al., 2006). As described, a distinguishing property of 5-HT DR neurons is the almost complete lack of firing during REM sleep, and in this respect, discharge is inversely correlated with certain events of REM, notably the PGO spikes of REM sleep (McCarley & Massaquoi, 1992; Sanford et al., 1994; Sanford, Tejani-Butt, Ross, & Morrison, 1996; Saper, Fuller, Pedersen, Lu, & Scammell, 2010; Vertes, 1990). This inverse relationship, together with the demonstration that DR stimulation or 5-HT agonists suppress PGO spikes while 5-HT antagonists enhance them (Callaway, Lydic, Baghdoyan, & Hobson, 1987), demonstrates a direct modulatory role for DR in PGO spike generation. Finally, it has been shown that the discharge of DR neurons is also inversely correlated with the spindles of SWS. Trulson and Jacobs (1979) described a reduction in DR activity immediately preceding spindles, which was maintained throughout spindling and followed by a pronounced rebound in firing at the termination of spindle activity. Consistent with this, serotonin or 5-HT agonists inhibit spindling (Contreras, Destexhe, Sejnowski, & Steriade, 1996; Lee & McCormick, 1996). In effect, then, DR is positioned to strongly suppress spindles

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of NREM sleep—likely through actions on the reticular nucleus of the thalamus (McCormick & Wang, 1991; Rodríguez et al., 2011; Steriade, 2004; Ursin, 2002). 2 Median Raphe Nucleus As described, the MR, along with the DR, is a major source of 5-HT input to the forebrain. By comparison with DR, however, much less attention has been paid to the role of the MR in the modulation of states of vigilance/sleep. An early report by Jacobs and colleagues (Rasmussen et al., 1984) described a population of putative 5-HT neurons of MR that displayed a very similar pattern of activity to “classic” 5-HT DR neurons. Specifically, these neurons fired at low tonic rates in quite waking and showed progressive decreases in rates in SWS and REM sleep, with a virtual cessation of activity in REM sleep. Subsequent studies, however, have identified a much more heterogeneous population of MR neurons with discharge profiles indicative of serotonergic and GABAergic MR neurons (see below). Possibly, the function most closely associated with MR and sleep is the modulation of the hippocampal EEG—or the theta rhythm. Specifically, the MR suppresses (or blocks) theta in NREM sleep, while MR silencing in REM sleep releases theta during that state (permissive role) (Vertes, 2010; Vertes et al., 2004). As is well recognized, theta is a prominent event of REM sleep (Bland & Oddie, 2001; Headley & Pare, 2017; Vertes, 2005; Vertes et al., 2004). As briefly discussed, theta is controlled by an ascending brainstem to septohippocampal system, that is, cells of RPO in the pontine RF fire at high tonic rates during theta-associated states, transfer this tonic discharge to the supramammillary nucleus (SUM), where it is converted to a (theta) rhythmic pattern of activity that is then relayed to medial septal “pacemaker cells” to generate theta in the HF (Bland & Colom, 1993; Bland, Oddie, Colom, & Vertes, 1994; Colom & Bland, 1987; Ford, Colom, & Bland, 1989; Oddie, Bland, Colom, & Vertes, 1994; Vertes, 1981, 2010). By comparison with this ascending theta-generating system, the MR (and its targets) represents an ascending hippocampal desynchronizing system. MR disrupts (or blocks) theta by suppressing some or all of the thetagenerating sites—RPO, SUM, the medial septum, or the hippocampus. Specifically, MR stimulation desynchronizes the hippocampal EEG, and MR lesions produce continuous theta independent of behavior (Assaf & Miller, 1978; Maru, Takahashi, & Iwahara, 1979; Vertes, 1981, 2010; Vertes et al., 2004; Yamamoto, Watanabe, Oishi, & Ueki, 1979). Further, the persistent theta produced by MR lesions can be reversed with infusions of the serotonin precursor, 5-HTP, and the depletion of 5-HT stores with PCPA attenuates the desynchronizing effects of MR stimulation (McNaughton, Azmitia, Williams, Buchan, & Gray, 1980; Yamamoto et al., 1979). In accord with the

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foregoing, we more recently demonstrated that infusions of the GABAA agonist, muscimol, or the 5-HT1A autoreceptor agonist, 8-OH-DPAT, into MR produced continuous theta in anesthetized rats (Kinney, Kocsis, & Vertes, 1994, 1995, 1996; Vertes, Kinney, Kocsis, & Fortin, 1994). Finally, Varga, Sik, Freund, and Kocsis (2002) reported that MR neurons express GABAB receptors and infusions of the GABAB agonist, baclofen, into MR produced longlasting theta that “resulted from suppression of the serotonergic output from the median raphe.” The discharge properties of MR neurons are also consistent with its role in the modulation of the hippocampal EEG. For instance, we demonstrated that about 80% of MR neurons displayed firing properties associated with changes in theta/hippocampal EEG (Kocsis & Vertes, 1996; Viana Di Prisco, Albo, Vertes, & Kocsis, 2002). MR cells consisted of three major types, two of which were putative serotonergic neurons based on their slow, regular rate of discharge. The 5-HT cells were found to be “theta-off” cells, that is, they were active during the nontheta state of NREM sleep and virtually silent during REM sleep—thus permissive to theta of that state. A second major class of MR cells, putatively GABAergic neurons, fired at high rates during REM sleep (theta-on, REM-on cells) and was thought to inhibit 5-HT MR (theta-off ) cells to generate theta in REM (Vertes, 2010; Viana Di Prisco et al., 2002; Fig. 7.6). It has further recently been shown that MR activity is inversely related to hippocampal sharp waves/ripples of NREM sleep (Maier & Kempter, 2017; ul Haq et al., 2016; Wang et al., 2015). For instance, Wang et al. (2015) reported, in freely behaving mice, that (1) putative serotonergic and nonserotonergic MR neurons show reduced activity prior to the onset of ripple activity, (2) optogenetic MR stimulation suppressed ripple activity, and (3) optogenetic inhibition of MR neurons enhanced sharp waves/ ripples during NREM sleep. These findings, together with those on theta, suggest that 5-HT MR neurons suppress theta and sharp waves/ripples during NREM sleep—with the corollary that the inhibition of MR releases both types of activity in NREM or REM sleep.

VI SEROTONERGIC MODULATION OF SLEEP A NREM Sleep As described below, the well-characterized “flip-flop” model of Saper and colleagues has clear heuristic value in defining alternations of sleep-wake states (Lu, Sherman, Devor, & Saper, 2006; Saper, Cano, et al., 2005; Saper et al., 2010). The model is based on the demonstration of anatomical and physiological interactions between arousal and sleep structures. In brief, during waking,

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FIG. 7.6 (A) The discharge characteristics of a slow-firing (SF) cell of the median raphe nucleus that decreased in discharge from nontheta (left side) to theta elicited with tail pinch (TP, horizontal gray bar). (B) Superimposed action potentials of the theta-off cell (A) showing a wide spike (2 ms) and interspike interval histogram (ISIH) demonstrating the slow rate of firing of the cell (1.2 Hz) (0.8 s peak in ISIH) during nontheta conditions. (C) Superimposed action potentials of the SF theta-on cell of (D) showing a wide spike (2 ms) and the ISIH demonstrating enhanced firing of the cell to 2.4 Hz (0.4 s peak in ISIH) in the 10 s period following TP-elicited theta. (D) The discharge properties of the SF theta-on cell of C showing increased rates of firing during TP-elicited theta. Figure adapted from Viana Di Prisco, G. V., Albo, Z., Vertes, R. P., & Kocsis, B. (2002). Discharge properties of neurons of the median raphe nucleus during hippocampal theta rhythm in the rat. Experimental Brain Research, 145, 383–394.

monoaminergic (DR, LC, and TMN) and cholinergic (LDT/PPT) nuclei of the brainstem and hypothalamus activate the thalamus, basal forebrain, and cortex to initiate and maintain states of arousal (Berridge, 2008; Jacobs & Fornal, 2010; Jones, 2004, 2005; McCormick & Bal, 1997; Robbins, 1997). The “arousal groups” are, in turn, driven (or further enhanced) by ORX neurons of the LHy to produce consolidated periods of waking,

especially during conditions requiring a high degree of alertness (Brown, Sergeeva, Eriksson, & Haas, 2002; Eggermann et al., 2001; Hagan et al., 1999; Horvath, Diano, & Van Den Pol, 1999; Inutsuka & Yamanaka, 2013; Korotkova, Sergeeva, Eriksson, Haas, & Brown, 2003; Liu et al., 2002; Peyron et al., 1998; Takahashi, Koyama, Kayama, & Yamamoto, 2002; Xi, Morales, & Chase, 2001; Yamanaka et al., 2002).

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In addition to activating effects on the forebrain, the arousal-related nuclei exert inhibitory actions on sleepinducing sites of the basal forebrain (BF) to thereby suppress them and maintain wakefulness. The principal BF structure responsible for controlling NREM sleep is the VLPO (Saper, Cano, et al., 2005; Saper et al., 2010; Scammell, Arrigoni, & Lipton, 2017). VLPO is suppressed in waking (mainly by monoaminergic nuclei) and, in turn, inhibits DR/LC/TMN and ORX neurons during the induction of NREM sleep—a reciprocal, mutual inhibitory network (Gaus, Strecker, Tate, Parker, & Saper, 2002; Lu, Greco, Shiromani, & Saper, 2000; Sherin et al., 1998). Interestingly, Szymusiak, Alam, Steininger, and McGinty (1998) provided early evidence, in freely behaving rats, that VLPO neurons discharge in an inverse manner to that of DR neurons. Specifically, VLPO cells fired at very low rates during waking, with marked and progressively increasing rates at the onset and throughout NREM sleep—with peak firing during the deepest stages of SWS. VLPO neurons were also shown to be responsive to long periods of sleep deprivation, that is, they exhibited a steady increase in discharge rate as sleep pressure intensified (Sherin, Shiromani, McCarley, & Saper, 1996; Szymusiak et al., 1998). It is well recognized that sleep pressure is directly related to the duration of wakefulness, as there is a progressive buildup during waking of “sleep substances” (or somnogens) that act to induce sleep, the best characterized being adenosine (see Chapter 8, this volume). Adenosine appears to exert direct and indirect effects, via two mechanisms, in the control of sleep. Specifically, through the activation of adenosine A1 receptors, adenosine directly inhibits hypothalamic “arousal” sites, mainly histaminergic TMN and ORX cells (Liu & Gao, 2007; Oishi, Huang, Fredholm, Urade, & Hayaishi, 2008; Thakkar, Engemann, Walsh, & Sahota, 2008; Yum et al., 2008). In a complementary manner, mediated by A2 receptors, adenosine activates VLPO neurons—putatively through the inhibition of GABAergic neurons, thus disinhibiting VLPO cells (Chamberlin et al., 2003; Morairty, Rainnie, McCarley, & Greene, 2004; Scammell et al., 2001). Accordingly, as sleep pressure builds during waking, adenosine (and other somnogens) accumulates to exert a dual effect: (1) directly inhibit the arousal network (2) and activate (via disinhibition) VLPO neurons to suppress monoaminergic and ORX cells to induce NREM sleep (Donlea, Alam, & Szymusiak, 2017). With respect to the role of serotonin, Gallopin et al. (2000) initially reported that norepinephrine inhibited VLPO neurons in vitro, while the effects of serotonin were less pronounced. In a follow-up study, however, two different types of VLPO neurons were identified, based on their response to serotonin—type 1 and type 2 cells (Gallopin et al., 2005). While norepinephrine inhibited all VLPO neurons, type 1 cells (which

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comprised about 50% of recorded cells) were also suppressed by serotonin. Type 2 VLPO cells, on the other hand, showed progressive “increases” in the rate of firing following the application of serotonin. Interestingly, type 2 cells were also excited by the activation of adenosine A2 receptors. Accordingly, VLPO-induced sleep was thought to involve the coordinated actions of these two populations of VLPO cells. Specifically, type 2 VLPO neurons are active during waking, in part driven by 5-HT input. As adenosine levels steadily increase during periods of alertness/waking, adenosine binds to VLPO A2 receptors to further activate type 2 neurons, thus shifting the organism into a state of “drowsiness.” This effect mainly involves type 2-mediated suppression of the “arousal network” to “flip the switch” to stage 1 NREM sleep. As type 1 VLPO neurons become disinhibited via the gradual removal of inhibitory inputs from monoaminergic and cholinergic nuclei to VLPO, they become progressively more active, to thus maintain the state of NREM sleep (Gallopin et al., 2005). More recently, Rancillac and colleagues (Sangare, Dubourget, Geoffroy, Gallopin, & Rancillac, 2016) examined 5-HT receptor expression of VLPO neurons and reported that (1) both types(1 and 2) of VLPO neurons expressed several 5-HT receptor profiles but 5-HT1 mRNA was only expressed in type 1 neurons, (2) the inhibition of type 1 VLPO neurons was mediated via 5-HT1A receptors, and (3) type 2 neurons were selectively excited by the 5-HT2C agonist, PFO3246799. The latter finding suggests that serotonin, acting through 5-HT2C receptors on type 2 VLPO neurons, might trigger the onset of NREM sleep. Supporting this, Frank, Stryker, and Tecott (2002) reported that mice lacking the 5-HT2C receptor spent a greater amount of time in waking, less in NREM sleep, and showed fewer transitions from NREM to REM sleep. The mice also exhibited an altered response to sleep deprivation, suggesting that 5-HT2C receptors (possibly on VLPO neurons) may also participate in the homeostatic drive to sleep (Frank et al., 2002). The dual nature of 5-HT actions on sleep/waking states highlights the need to revisit the role of serotonin in sleep (Gallopin et al., 2000, 2005; Sangare et al., 2016). In fact, Jouvet (1999) reconsidered the role of serotonin and sleep, suggesting that serotonin may serve to initiate (or trigger) sleep, rather than to primarily maintain sleep. For instance, recognizing the steady discharge of DR cells in waking, Jouvet (1999) stated the following: “thus, it may be postulated that some 5-HT neurons (n. raphe dorsalis) that fire regularly in a clocklike fashion during waking may be participating in the process (sleep) by measuring both the duration and the intensity of waking. The liberation of 5-HT during waking in a strategic location of the anterior hypothalamus might herald a cascade of postsynaptic genomic events that will trigger

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sleep onset.” In effect, following sustained waking, serotonin may promote/initiate sleep through actions on BF sleep centers (Fig. 7.7). Noteworthy in this regard is the MnPO, which, together with VLPO, comprises the sleep control center of the forebrain. In contrast to VLPO, however, MnPO neurons show increased rates of discharge at the onset and during the initial stages of NREM, followed by a steady decline throughout sleep (McGinty et al., 2004). The DR is reciprocally connected with the MnPO and, accordingly, may represent an important influence on MnPO in the transition from waking to NREM sleep—but with little or no involvement in sustaining NREM sleep.

B REM Sleep As mentioned, a prominent feature of DR and MR neurons is their virtual silence during REM sleep (Jacobs & Azmitia, 1992; Jacobs & Fornal, 2008, 2010). An early and still oft-cited model for REM sleep control is the “reciprocal interaction hypothesis” of Hobson and McCarley. Although the model has been revised and updated (see below), the original version essentially involved the reciprocal actions of monoaminergic and cholinergic nuclei in REM sleep cycling (Hobson, McCarley, & Wyzinski, 1975; Hobson, PaceSchott, & Stickgold, 2000; McCarley & Hobson, 1975; Steriade & Hobson, 1976). In its classic form, the model predicts that, during non-REM states (waking and SWS), serotonergic DR neurons and noradrenergic LC cells inhibit brainstem cholinergic cells to block the occurrence of REM sleep. It was originally erroneously claimed that the ACh cells responsible for REM were those of the medial pontine RF (or RPO), but have subsequently been shown to be the ACh cells of the LDT and PPT of the dorsolateral pons (McCarley, Greene, Rainnie, & Portas, 1995). During REM, LDT/PPT cells become highly active, due to the removal of inhibitory actions of DR/LC cells (disinhibition)—as the monoaminergic neurons are silenced in REM. Accordingly, DR (and LC) cells have been defined as “REM-off” cells discharging in an opposing manner to the “REM-on” cells of the LDT/PPT (Hobson et al., 1975, 2000; McCarley & Hobson, 1975; Thakkar, Stecker, & McCarley, 1998). A considerable body of evidence supports the basic elements of the model. For instance, subsets of cholinergic LDT/PPT neurons have been shown to discharge selectively in REM sleep, and ACh agonists or antagonists produced increases or decreases in the activity of these cells, respectively (Brown et al., 2012; Steriade & McCarley, 1990). Moreover, enhancing DR/LC actions on LDT/PPT neurons suppresses REM sleep; reducing their effect promotes REM (McCarley et al., 1995; Ursin, 2002). Serotonergic actions on LDT/PPT cells appear

mainly mediated by 5-HT1A receptors, as activating these receptors in vitro strongly hyperpolarized ACh LDT neurons (Leonard & Llinas, 1994; Luebke et al., 1992; Monti & Jantos, 2004; Muhlethaler, Khateb, & Serafin, 1990). As indicated, the discharge rate of DR (and LC) neurons progressively decreases from NREM to REM sleep, which has partly been attributed to the progressive development of intrinsic inhibitory interactions among DR cells—largely mediated by 5-HT1A autoreceptors on DR (and MR) neurons (Barnes & Sharp, 1999; Leonard, 1996; Monti, 2010a, 2010b, 2011). 5-HT1A agonists applied to DR neurons hyperpolarize them, leading to a net suppression of DR activity. Further, infusions of the 5-HT1A receptor agonist, 8-OH-DPAT, into the DR of cats produced a marked reduction of extracellular 5-HT (Portas & McCarley, 1994), and the activation of 5-HT1A receptors resulted in a 300% increase in amounts of REM sleep (McCarley et al., 1995). The basic findings that 5-HT1A receptor activation reduces 5-HT levels and enhances REM have been confirmed in several subsequent reports and are consistent with observations that 5-HT1A antagonists applied to DR greatly suppress REM sleep (Bjorvatn, Fagerland, Eid, & Ursin, 1997; Bjorvatn & Ursin, 1998; Fornal et al., 1994; Monti & Jantos 2005; Monti, Jantos, & Monti, 2002; Monti, Jantos, Monti, & Alvariño, 2000; Monti & Monti, 2000; Portas, Thakkar, Rainnie, & McCarley, 1996; Sørensen, Grønli, Bjorvatn, Bjørkum, & Ursin, 2001; Sørensen, Grønli, Bjorvatn, & Ursin, 2001). Although serotonergic effects on REM sleep appear to mainly involve 5-HT1A receptors, the 5-HT1B receptor also reportedly serves a role in REM—perhaps by opposing the effects of 5-HT1A receptors. For instance, Monti, Jantos, and Lagos (2010) showed that 5-HT1B agonists delivered to DR produced a significant reduction in REM sleep (rather than increases seen with 5-HT1A activation) and 5-HT1B antagonists blocked this effect. It was further demonstrated, however, that muscimol injected into DR blocked the suppressive actions of 5-HT1B agonists on REM sleep. This suggests that 5-HT1B effects may be mediated by GABAergic cells (Monti et al., 2010), that is, 5-HT1B inhibition of GABAergic DR neurons would disinhibit 5-HT DR cells; increase their firing rate; and, through effects on REM-generating sites, suppress REM sleep (Monti, 2011; Monti et al., 2010). The 5-HT2 receptor also appears to be involved in the suppression of REM sleep, acting through both 5-HT2A and 5-HT2C receptor mechanisms. Infusions of the 5-HT2A/2C agonist, DOI, into DR suppress REM sleep, and the effect can be attenuated with either 5-HT2A or 5-HT2C antagonists—indicating an involvement of both receptor subtypes (Monti & Jantos, 2006a, 2006b). Interestingly (and seemingly paradoxical), direct infusions of DOI into DR inhibit the firing of DR cells—which would normally trigger, rather than suppress, REM sleep (Garratt, Kidd, Wright, & Marsden, 1991). The most

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FIG. 7.7 Schematic diagram depicting the involvement of serotonin (5-HT) in waking (on the left) and NREM sleep (on the right). WAKE: During wakefulness, orexin (ORX) cells of the lateral hypothalamus (LHy) excite 5-HT neurons of the dorsal raphe (DR) and median raphe (MR) nuclei, noradrenergic (NE) neurons of the locus coeruleus (LC), and histaminergic cells of the tuberomammillary nucleus (TMN). The DR, MR, LC, TMN, and other brainstem “arousal groups” then activate neurons of the thalamus and basal forebrain to produce cortical EEG and behavioral arousal/wakefulness. Concomitantly, the brainstem “arousal nuclei” inhibit type 1 neurons of the ventrolateral preoptic area (VLPO) and median preoptic area (MnPO) to suppress sleep. NREM: Sleep pressure builds following extended periods of wakefulness, which results in the steady accumulation of sleep factors (or somnogens)—predominantly adenosine. Both 5-HT and adenosine, via A2 receptors, excite (type 2) VLPO neurons and, simultaneously, adenosine, via A1 receptors, inhibiting ORX neurons of the LHy and TMN to remove excitatory drive from the DR, LC, and other arousal brainstem nuclei. This further disinhibits VLPO neurons to initiate NREM sleep, and as VLPO activity progressively develops in NREM, GABAergic and galanin neurons of the VLPO further inhibit wake-promoting nuclei to maintain NREM sleep. Blue arrows indicate excitation. Red arrows indicate inhibition.

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parsimonious explanation is that 5-HT2 receptors, which are excitatory, are mainly expressed on GABAergic DR cells. The activation of GABAergic cells would inhibit serotonergic neurons but would exert a much greater inhibitory effect on LDT/PPT neurons, leading to the suppression of REM sleep (Monti, 2011). Supporting this, Amici et al. (2004) demonstrated that the infusion of 5-HT2 agonist, DOI, or the antagonist, ketanserin, into LDT/PPT produced decreases or increases, respectively, in REM sleep. Finally, GABAergic neurons of DR also express the 5-HT7 receptor, and infusions of 5-HT7 receptor agonists into DR suppress REM sleep, while 5-HT7 antagonists enhance it. The similarity of 5-HT7 and 5-HT2 effects suggests that 5-HT7 influences on REM are also mediated by GABAergic actions on the LDT/ PPT (Monti, Leopoldo, & Jantos, 2008). Whereas a 5-HT1A receptor-mediated (net) inhibition of serotonergic DR cells appears to be a primary mechanism for the silencing of DR neurons in REM sleep (Monti & Monti, 2000), other factors are also involved. For instance, in the original reciprocal interaction model (Hobson et al., 1975; McCarley & Hobson, 1975), REM-on LDT/PPT cells excited DR/LC neurons to terminate the REM cycle. However, this switch to terminate REM (via DR) would only occur after a marked buildup of LDT/ PPT activity near the end of the REM cycle. The buildup was augmented by mutual excitatory interactions between LDT/PPT and glutamatergic cells of the medial pontine RF. In a later revision of the model, DR/LC cells were held in check during REM by an ACh-elicited excitation of GABAergic neurons to inhibit DR cells. Extracellular levels of GABA in the brainstem significantly increase during REM sleep (McCarley et al., 1995). A key element of the flip-flop model is the reciprocal inhibitory actions of DR/LC and VLPO across sleep/ wake states. VLPO’s influence on DR cells would, in part, account for their slowing in NREM sleep. There is, however, a region of the forebrain adjacent to VLPO, termed “extended VLPO,” which is selectively active in REM sleep to thus exert a strong inhibitory influence on DR/ LC neurons in that state (Lu et al., 2002). With the foregoing taken into account, the virtual silence of DR neurons in REM sleep would involve (1) a mutual inhibitory network among DR cells, (2) an LDT/PPT-GABAergic-DR circuit suppressing DR neurons, and (3) the inhibitory actions of “extended VLPO” on DR cells. Although beyond the present scope, several additional areas of the brainstem have recently been shown to exert modulatory influences on REM sleep (for details, see Chapter 5, this volume). For instance, as indicated, forebrain structures (e.g., extended VLPO) have been implicated in NREM-REM transitions, and Saper and colleagues (and others) have further described a brainstem network involved in NREMREM cycling—similar to the flip-flop model (Lu et al.,

2006; Luppi et al., 2006). Accordingly, other brainstem structures promoting the transition to REM sleep (REM-on nuclei) are the precoeruleus region (PC), the medial peribrachial area (MPB), and the sublaterodorsal nucleus (SLD), and the main site for the transition to NREM sleep (or the suppression of REM) is the ventrolateral periaqueductal gray (vlPAG) (Lu et al., 2006). These structures reportedly interact with each other and with the “classic” brainstem sites (LDT, PPT, DR, and LC) in the control of NREM/REM sleep cycling (Luppi et al., 2012; Saper et al., 2010; Scammell et al., 2017) (Fig. 7.8). With respect to a 5-HT DR influence on this expanded network, DR strongly distributes to vlPAG (Clements, Beitz, Fletcher, & Mullett, 1985; Vertes & Kocsis, 1994), and Saper and colleagues proposed that 5-HT DR cells activate vlPAG neurons to suppress REM sleep (Lu et al., 2006). As such, the (relatively) high firing rates of DR in waking and NREM (compared with REM) would, via connections with vLPAG, suppress REM sleep in these states. The reduction (or silencing) of DR cells in REM sleep would remove excitatory drive to vlPAG cells, reduce their activity, and disinhibit PC/MPB/SLD cells (and likely LDT/PPT neurons) in the transition from NREM to REM sleep. The DR mutually interacts with two special groups of the LHy in the modulation of REM sleep: MCH and ORX neurons. As previously discussed, ORX has been characterized as the “master switch” for wakefulness, as it drives other “waking” regions (including DR) to trigger and maintain wakefulness. The firing of MCH cells, on the other hand, appears to be a mirror image of the activity of monoaminergic/DR neurons across sleep/wake states. For instance, Hassani, Lee, and Jones (2009) reported that MCH cells fire at low rates in waking, steadily increase their discharge in NREM sleep, and show dramatic increases in firing rates in REM sleep. Consistent with this discharge profile, the activation of MCH neurons produces modest increases in NREM but large (up to 95%) increases in REM sleep, whereas their suppression markedly increases waking, with associated reductions in NREM and REM sleep (Ahnaou et al., 2008; Jego et al., 2013; Konadhode et al., 2013; Peyron, Sapin, Leger, Luppi, & Fort, 2009; Tsunematsu et al., 2014; Verret et al., 2003). Interestingly, microinfusions of MCH into the DR (or LC) produce pronounced increases in REM, with smaller increases of NREM sleep. This suggests that the effects of MCH on REM sleep may largely be mediated by DR/LC. As the MCH and DR are reciprocally linked (Yoon & Lee, 2013), an activation of DR neurons in waking would inhibit MCH cells (wake off/REM-on neurons) (van den Pol, Acuna-Goycolea, Clark, & Ghosh, 2004) and, at the same time, activate vlPAG cells to suppress REM sleep (see above) (Lu et al., 2006; Vetrivelan, Chang, & Lu, 2011). During NREM sleep, as VLPO

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FIG. 7.8 Schematic diagram depicting the involvement of serotonergic REM-off states (on the left) and REM-on states (on the right). REM-off: During REM-off states, 5-HT neurons of the dorsal (DR) and median (MR) raphe nuclei inhibit the acetylcholine (ACh) containing REM-on neurons of the laterodorsal tegmental (LDT) and the pedunculopontine (PPT) nuclei, as well as melanin-concentrating hormone (MCH) neurons of the lateral hypothalamus (LHy). Concomitantly, DR and LC cells send excitatory projections to the ventrolateral periaqueductal gray (vlPAG) that, via GABAergic projections, exerts inhibitory actions on the medial peribrachial nucleus (MPB), sublaterodorsal nucleus (SLD), and other REM-on brainstem nuclei, to maintain the REM-off state. REM-on: During NREM sleep, the firing rates of DR and LC decrease, due in part from inhibition from the ventrolateral preoptic area. This attenuates the 5-HT and NE inhibition of MCH neurons of the LHy, which results in a progressive increase in the firing rate of MCH neurons to inhibit DR/LC cells (to near silence) and to thus disinhibit REM-on neurons of the LDT and PPT, resulting in the initiation and maintenance of the REM sleep state. The MCH also directly inhibits the vlPAG, resulting in the disinhibition of the SLD and MPB to further consolidate REM sleep. LDT/PPT drives various events of REM including, as shown, PGO waves and muscle atony of REM sleep. Blue arrows indicate excitation. Red arrows indicate inhibition.

(and associated regions) suppress ORX neurons and their targets, DR neurons would slow, thus reducing inhibitory control over MCH cells. As MCH activity steadily increased, it would suppress DR/LC discharge resulting in (1) the removal of DR/LC inhibitory influences on LDT/PPT and (2) a reduced activation of vlPAG (which inhibits REM-on centers) (Devera et al., 2015; Lagos et al., 2009, 2011; Luppi, Peyron, & Fort, 2013; Monti, Lagos, Jantos, & Torterolo, 2015). The net result would be a switch from NREM to REM sleep.

Acknowledgments We thank Ms. Amanda Rojas for her excellent assistance with the graphic illustrations. We also thank Ms. Rojas and Ms. Mary Gorora for their assistance in the preparation of the manuscript. This work was supported by NIMH grant MH099590 to RPV.

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