Hypocretin and the Regulation of Sleep-Wake Transitions

C H A P T E R

6 Hypocretin and the Regulation of Sleep-Wake Transitions Natalie Neva´rez, Luis de Lecea Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

I INTRODUCTION

in the same neurons and that their cell bodies were restricted to the hypothalamus and its projections (de Lecea et al., 1998). At the same time, Masashi Yanagisawa’s research team at Texas Southwestern identified a novel family of hypothalamic neuropeptides that bound to two orphan G-protein-coupled receptors (GPCRs). When these neuropeptides were injected intracerebroventricularly, they elicited feeding behavior. Based on these findings, the group named these peptides “orexins,” from the Greek word for appetite “orexis” (Sakurai et al., 1998). As research has distinguished a role for Hcrt in physiological processes beyond feeding, we will refer to these peptides as the hypocretins. Hcrt neurons increase firing rates during active waking, reduce activity during quiet wakefulness, and have low activity during non-rapid eye movement (NREM) sleep and no activity during REM sleep (Hassani, Lee, & Jones, 2009; Lee, Hassani, & Jones, 2005; Mileykovskiy, Kiyashchenko, & Siegel, 2005; Takahashi, Lin, & Sakai, 2008). Optogenetic manipulations of Hcrt circuitry have shown that stimulation of this neural population induces wakefulness in mice, while its inhibition promotes nonREM sleep (NREM; also known as slow-wave sleep (SWS)) (Adamantidis et al., 2007; Tsunematsu et al., 2013). Studies utilizing excitatory designer receptors exclusively activated by designer drugs (DREADDs) show that injections of the ligand clozapine-n-oxide (CNO) promote wakefulness in mice expressing excitatory (Gq) DREADDs in Hcrt neurons, while engagement of inhibitory (Gi) DREADDs results in decreased wakefulness and increased time in NREM sleep (Sasaki et al., 2011). It is important to note, however, that mice that lack Hcrt neurons or Hcrt-2 receptors show normal amounts of sleep, an effect that has been assessed in human patients as well (Branch et al., 2016; de Lecea & Sutcliffe, 2005).

In 1998, the hypocretins (Hcrt) were discovered almost simultaneously by two groups (de Lecea et al., 1998; Sakurai et al., 1998). Within 3 years, these peptides were linked to the devastating and poorly understood phenomenon of narcolepsy (Chemelli et al., 1999; Lin et al., 1999; Nishino, Ripley, Overeem, Lammers, & Mignot, 2000; Peyron et al., 2000). Subsequent research found a key role for these neuropeptides in the modulation of arousal states, and in 2007, the first in vivo use of optogenetics causally linked the Hcrt system to the regulation of sleep-to-wake transitions (Adamantidis, Zhang, Aravanis, Deisseroth, & de Lecea, 2007). Today, we recognize these neuropeptides as central regulators of generalized arousal and alertness, and the application of modern techniques continues to uncover the diverse roles of these neuromodulators.

A The Discovery of Hypocretin/Orexin It was quickly realized that both of the research groups mentioned above described the same peptides and had arrived at their findings via disparate routes. The first group, led by Gregor Sutcliffe at the Scripps Research Institute in La Jolla, California, was interested in characterizing peptides synthesized strictly within the hypothalamus. The group used subtractive RNA hybridization to characterize a cDNA clone within the dorsal and lateral hypothalamus that encoded a predicted preproprotein, which they named preprohypocretin. Preprohypocretin was the precursor to two peptides they named hypocretin-1 (Hcrt-1) and hypocretin-2 (Hcrt-2), due to their hypothalamic origin and similarity to the gut hormone, secretin. Further characterization showed that both peptides were found

Handbook of Sleep Research, Volume 30 ISSN: 1569-7339 https://doi.org/10.1016/B978-0-12-813743-7.00006-2

89

© 2019 Elsevier B.V. All rights reserved.

90

6. HYPOCRETIN AND REGULATION OF SLEEP-WAKE TRANSITIONS

This suggests that Hcrt alone is not responsible for sleep or wake states in and of itself, but may be contributing to these processes in a more nuanced fashion. Indeed, below, we will review data that show how the diverse actions of Hcrt may be a function of its activity at distinct projection sites, receptors, and its interactions with multiple neurotransmitter systems.

II BRIEF ANATOMY OF Hcrt CIRCUITRY Light and electron microscopy provided some of the earliest knowledge of afferents to and efferents from Hcrt neurons, revealing a widespread network with contributions from several neurotransmitter systems (de Lecea et al., 1998; Mintz, van den Pol, Casano, & Albers, 2001; Nambu et al., 1999; Peyron et al., 1998; Sakurai et al., 1998). Additionally, in vitro studies using receptor agonists and antagonists have shown the various interactions of Hcrt with other neurotransmitter systems (Hagan et al., 1999; Horvath et al., 1999; Takahashi, Koyama, Kayama, & Yamamoto, 2002; Xie et al., 2006). The information gained from these experiments has shown that Hcrt is aptly positioned to integrate information from various sleep-wake relevant circuits to influence neuronal excitability and subsequent behavior.

A Basic Neuroanatomical Characteristics of Hcrt Neurons Hypocretin cell bodies originate exclusively within the hypothalamus and project broadly throughout the brain and spinal cord (Baldo, Daniel, Berridge, & Kelley, 2003; Ciriello, Rosas-Arellano, Solano-Flores, & de Oliveira, 2003; Peyron et al., 1998). Quantification of Hcrt cell bodies has shown varying levels of expression, from very dense to very sparse in cell bodies in the hypothalamus of rats (Nambu et al., 1999). There are up to 5000 Hcrtcontaining cells within the hypothalamus of cats, with approximately 10 times more Hcrt neurons in humans (Nambu et al., 1999; Thannickal et al., 2000; Torterolo, Sampogna, Morales, & Chase, 2006). Hcrt perikarya are located most densely within the lateral hypothalamus (LH), with additional cell bodies located in the perifornical area and the dorsomedial, paraventricular, and the tuberal hypothalamus (Nambu et al., 1999; Thannickal et al., 2000). Importantly, among the dense efferent and afferent projections of Hcrt neurons, many fibers connect to wake-promoting regions, as discussed below in more detail (de Lecea et al., 1998; Nambu et al., 1999).

III FUNCTIONAL CIRCUITRY OF Hcrt-MEDIATED AROUSAL Hcrt neurons exist as a node within a highly interconnected brain network for the regulation of arousal. Major

sleep-/wake-relevant projections to Hcrt neurons include the dorsomedial hypothalamus (DMH), the ventrolateral preoptic area (vlPOA), and the basal forebrain (BF) (Yoshida, McCormack, España, Crocker, & Scammell, 2006). While Hcrt cell bodies are restricted to the hypothalamus, Hcrt axons project widely in the brain. Major excitatory efferents target, among others, the noradrenergic locus coeruleus (LC), serotonergic dorsal raphe nucleus (DRN), cholinergic nuclei in the brain stem and BF, and histaminergic tuberomammillary nucleus (TMN). Additionally, Hcrt excites dopaminergic neurons within the ventral tegmental area (VTA). Below, we will focus on some key regions of the hypocretin-mediated arousal circuit; however, this is not an exhaustive survey of cell types and molecular players in these processes, and we direct the reader to additional readings on these topics (Datta & Maclean, 2007; Jones, 2017).

A Locus Coeruleus (LC) Activity of noradrenergic neurons in the LC contributes to wakefulness and arousal (Aston-Jones & Cohen, 2005; Berridge & Waterhouse, 2003). LC noradrenergic neurons display tonic firing during wakefulness, low activity during SWS, and cease activity during REM sleep (Aston-Jones & Bloom, 1981; Carter et al., 2010; Hobson, McCarley, & Wyzinski, 1975; Rasmussen, Morilak, & Jacobs, 1986). Pharmacological inhibition of LC neurons via clonidine increases NREM sleep (De Sarro, Ascioti, Froio, Libri, & Nisticò, 1987). Thus, activity of these neurons may promote wakefulness, while their inhibition may promote sleep. Immunocytochemistry has characterized major innervation of the LC by Hcrt in rats and monkeys, and in vitro application of Hcrt to LC neurons increases the frequency of action potentials (Hagan et al., 1999; Horvath et al., 1999; Peyron et al., 1998). Similarly, in vivo administration of Hcrt into the LC increases firing rates, while optogenetic silencing of LC neurons with concurrent excitation of Hcrt cells inhibits Hcrt-evoked sleep/ wake transitions (Carter et al., 2010, 2012; Gompf & AstonJones, 2008). In support of this, depolarizing LC neurons below threshold increases the probability of Hcrt-induced sleep/wake transitions (Carter et al., 2010, 2012). Importantly, these studies showed a frequency-dependent effect for stimulation of LC neurons whereby, as the frequency of stimulation increased, the number of pulses required to achieve 100% probability of awakening decreased for both NREM and REM sleep (Carter et al., 2010). These data position the LC as a critical hub for hypocretin-mediated arousal.

B Dorsomedial Hypothalamus (DMH) DMH projections onto Hcrt neurons are thought to relay time-of-day signals from the master circadian clock (located in the suprachiasmatic nucleus (SCN)),

PART B. REGULATION OF WAKING AND SLEEPING

III FUNCTIONAL CIRCUITRY OF Hcrt-MEDIATED AROUSAL

especially signals relevant to food-entrainable circadian oscillations. Hcrt administered into the LH elevates c-fos immunoreactivity in the DMH, and injections of Hcrt-1 into the DMH result in increased feeding in rats (Dube, Kalra, & Kalra, 1999; Mullett, Billington, Levine, & Kotz, 2000). Indeed, a 24 hour fast results in a threefold increase in c-fos expression in Hcrt neurons in rodents and nonhuman primates (Bernardis & Bellinger, 1998; Chou et al., 2003; Diano, Horvath, Urbanski, Sotonyi, & Horvath, 2003). Additionally, ablation of Hcrt neurons reduces food-entrained locomotor activity under conditions of restricted feeding and alters the expression of mNpas2 mRNA, which is a transcription factor thought to be involved in the regulation of food-entrainable oscillators (Akiyama et al., 2004). Interactions between foodentrainable oscillators and Hcrts are thought to involve interactions with neuropeptide Y (NPY)-expressing cells, as Hcrt neurons in the LH receive terminal appositions from NPY immunoreactive fibers, and cells reactive for Hcrt are also activated by NPY (Sakurai et al., 2005). NPY is a neuropeptide critical for feeding behavior in a variety of species (Sahu & Kalra, 1993). Thus, DMH projections onto Hcrt neurons and their subsequent relay to the LC may underlie feeding-mediated regulation of arousal.

C Ventrolateral Preoptic Area (vlPOA) Sleep-active GABAergic neurons of the vlPOA and Hcrt neurons of the LH interact to exert opposing influences on sleep and wakefulness. vlPOA neurons show sleep-wake state-dependent firing patterns, whereby 84% of POA neurons show greater activity during SWS and REM sleep relative to activity during waking (Kaitin, 1984; Koyama & Hayaishi, 1994). These neurons are implicated in overall sleep maintenance, as they increase activity in response to increasing homeostatic pressure for sleep and their stimulation initiates NREM sleep in cats and mice (Hernández Peón & Chávez Ibarra, 1963; Saper & Fuller, 2017; Schwartz & Kilduff, 2015; Sterman & Clemente, 1962). Optogenetic stimulation of vlPOA neurons results in increased NREM sleep, while lesions to the region result in sleeplessness and decrease in NREM sleep of up to 60% (Kaitin, 1984; Lu, Greco, Shiromani, & Saper, 2000; Saito et al., 2013). Within the LH, axons from the vlPOA have been observed in close proximity to Hcrt neurons, and optogenetic stimulation of the vlPOA results in the rapid inhibition of Hcrt neurons, suggesting that vlPOA neurons may function to promote sleep via inhibition of the LH Hcrt system (Saito et al., 2013; Sakurai et al., 2005; Uschakov, Gong, McGinty, & Szymusiak, 2007; Xie et al., 2006; Yoshida et al., 2006).

D Basal Forebrain (BF) The BF sends cholinergic, GABAergic, and glutamatergic inputs to Hcrt neurons, by which it can regulate sleep

91

and wakefulness. Reciprocally, Hcrt sends projections to cholinergic neurons within the BF (Chemelli et al., 1999; Eggermann et al., 2001; Ohno, Hondo, & Sakurai, 2008; Peyron et al., 1998). Injection of Hcrt-1 into the BF induces wakefulness, while lesions of the area result in a “comalike” state (Buzsaki et al., 1988; España, Baldo, Kelley, & Berridge, 2001; Fuller, Sherman, Pedersen, Saper, & Lu, 2011). Cholinergic neurons of the BF show maximal responses during waking and REM sleep and cease activity during NREM (Lee, Hassani, Alonso, & Jones, 2005; Xu et al., 2015). Optogenetic activation of this cell population results in immediate transitions to waking or REM sleep from SWS (Han et al., 2014; Irmak & de Lecea, 2014; Xu et al., 2015). Interestingly, it has been recently suggested that the faster-acting glutamatergic and GABAergic circuitry within the BF are likely to regulate sleep/wake transitions (Saper & Fuller, 2017). This increases the complexity of the arousal system within the BF, as GABAergic and glutamatergic neurons in the region show differing activity profiles across arousal states. Manipulations of GABAergic neurons in the BF have shown that chemogenetic activation results in wakefulness, while their inhibition induces NREM sleep (Anaclet et al., 2015). Adding to the complexity, subsets of GABAergic neurons in the region show a diversity of responses across arousal states (Duque, Balatoni, Detari, & Zaborszky, 2000; Jones, 2017; Lee, Hassani, Alonso, et al., 2005). Activation of somatostatin (SOM)+ GABAergic neurons promotes NREM sleep, while parvalbumin (PV)+ GABAergic neurons are most active during wakefulness and REM sleep (Han et al., 2014; Irmak & de Lecea, 2014; Kim et al., 2015; Xu et al., 2015). Likewise, the few manipulations that have targeted BF glutamatergic neurons have also arrived at ambiguous findings. While optogenetic stimulations of glutamatergic BF neurons induce immediate sleep-to-wake transitions, chemogenetic manipulations do not impact sleep architecture (Anaclet et al., 2015). Indeed, the heterogeneity of the BF underlies its complex modulation of distinct arousal states. Thus, future work should focus on how the heterogeneity of the region contributes to Hcrt-dependent arousal via further investigations of real-time cell activity and targeting of cell populations based on multiple, rather than a single, genetic targets.

E Dorsal Raphe Nucleus (DRN) Serotonergic neurons in the DRN likely play an important role in promoting wakefulness (McGinty & Harper, 1976; for details, see Chapter 7, this volume). Photostimulation of serotonergic cells in the DRN results in transitions from NREM sleep to active wakefulness (Cho et al., 2017; Moriya et al., 2017). In vitro studies have found that these neurons do not fire spontaneously; thus, they require excitation from afferent inputs (Vandermaelen & Aghajanian, 1983). Indeed, Hcrt may

PART B. REGULATION OF WAKING AND SLEEPING

92

6. HYPOCRETIN AND REGULATION OF SLEEP-WAKE TRANSITIONS

be the excitatory mechanism by which DRN cells coordinate wakefulness, as the addition of Hcrt to bath solutions containing DRN neurons increases their firing rate (Brown, Sergeeva, Eriksson, & Haas, 2002; Kohlmeier, Inoue, & Leonard, 2004; Kohlmeier, Watanabe, Tyler, Burlet, & Leonard, 2008). Interestingly, this effect may be state-dependent, as Hcrt release during wake may favor phasic activity of DRN serotonergic neurons, as is suggested by findings that Hcrt increases high-frequency inputs to the DRN, resulting in EEG activity similar to that of waking (Ishibashi et al., 2015, 2016). However, to better understand this circuit, DRN-stimulated wakefulness should be examined alongside Hcrt manipulations in vivo.

F Tuberomammillary Nucleus (TMN) Activity of TMN histaminergic neurons coincides with wake onset and is absent during both REM and NREM sleep (Haas & Panula, 2003; Takahashi, Lin, & Sakai, 2006). Hcrt activates TMN neurons, which subsequently release histamine at their terminals (Bayer et al., 2001; Eriksson, Sergeeva, Brown, & Haas, 2001; Huang et al., 2001). Optic inhibition of histaminergic TMN neurons inhibits wakefulness and induces NREM sleep (Fujita et al., 2017). Importantly, however, mice that lack the rate-limiting enzyme in histamine synthesis (histamine decarboxylase) show normal sleep-to-wake transitions, and optogenetic stimulation of Hcrt neurons increases probability of sleep-to-wake transitions in histaminedeficient mice and zebra fish (Carter, Adamantidis, Ohtsu, Deisseroth, & de Lecea, 2009; Chen, Singh, Oikonomou, & Prober, 2017). These data suggest that the TMN may serve a modulatory or redundant function in Hcrt-mediated arousal.

G Ventral Tegmental Area (VTA) The mesolimbic dopamine (DA) system is a key region for reward processing and learning (Berridge & Robinson, 1998; Schultz, 1998). Heightened arousal states aid in monitoring reinforcers and facilitate learning (Oleson, Gentry, Chioma, & Cheer, 2012). Additionally, motivational states impact arousal so as to facilitate the seeking of rewards and the avoidance of punishments (Mahler, Moorman, Smith, James, & Aston-Jones, 2014; for details, see Chapter 35, this volume). Unsurprisingly, this region is highly involved in the regulation of arousal states, in ways that we are only beginning to understand. During wakefulness, DA neurons are activated by a variety of salient stimuli, including natural and drug rewards and reward-predicting cues (Cone, McCutcheon, & Roitman, 2014; España, Melchior, Roberts, & Jones, 2011; Sheng, Santiago, Thomas, & Routh, 2014; Tung et al., 2016). VTA DA neurons exhibit burst firing during REM sleep, and their chemogenetic activation produces wakefulness

in mice (Dahan et al., 2007; Oishi et al., 2017). Further, optogenetic activation of DA neurons in the VTA induces wakefulness from a state of generalized anesthesia and maintains wakefulness even under conditions of increased sleep pressure (Eban-Rothschild, Rothschild, Giardino, Jones, & de Lecea, 2016; Oishi et al., 2017; Taylor et al., 2016). Thus, the VTA may be a key region for Hcrt to influence motivated arousal. Hcrt efferents from the LH innervate midbrain DA neurons, and DA cell bodies express Hcrt receptors (Baldo et al., 2003; Fadel & Deutch, 2002; Peyron et al., 1998). Whole-cell patch-clamp recordings in the VTA show that treatment with Hcrt-1 and Hcrt-2 increases DA neuron firing (Korotkova, Sergeeva, Eriksson, Haas, & Brown, 2003). Hcrt application in the VTA results in increased locomotion and stereotypy, and DA blockade abolishes this effect in rats (Nakamura et al., 2000). Hcrt-1 injections into the VTA increase time awake and levels of DA at its terminals in the prefrontal cortex (PFC) (Narita et al., 2006; Vittoz & Berridge, 2006). These data suggest a VTA DAergic-Hcrt mechanism by which external stimuli can influence arousal. Indeed, inhibition of VTA DA neurons promotes sleep, even in the presence of salient stimuli such as a novel conspecific, predator scent, and food, supporting a role for this region in the regulation of salience-induced arousal (Eban-Rothschild et al., 2016). We are only beginning to understand the mesolimbic DAergic regulation of arousal states, but future work should undoubtedly investigate the interactions between Hcrt and DA circuitry in the regulation of arousal states, especially those influenced by internal and external motivating factors.

H Laterodorsal Tegmental Nucleus (LDT) Cholinergic LDT neurons are critical for the regulation of wakefulness. These neurons are active only during wakefulness and REM sleep (Boucetta, Cisse, Mainville, Morales, & Jones, 2014; Sakai, 2015). Chronic, lowamplitude stimulation (1 μA) of the LDT induces REM sleep (Thakkar, Portas, & McCarley, 1996). In cats, injection of Hcrt-1 into the LDT results in a significant increase in time spent in wakefulness and a decrease in time in REM sleep (Xi, Morales, & Chase, 2001). Measures of LDT neuronal activity in anesthetized animals show that treatment with Hcrt-1 results in long-lasting, moderate excitation, an effect that may be similar to that seen at LC and DRN neurons (Takahashi et al., 2002). Interestingly, only a subset of LDT neurons are Hcrt-receptive, and future work should characterize how cell diversity influences overall network activity and subsequent behavior.

IV DYSFUNCTION Above, we have discussed the numerous interactions among Hcrt and the other sleep-wake regulatory brain

PART B. REGULATION OF WAKING AND SLEEPING

93

V BEYOND SLEEP/WAKE

regions and neurotransmitter systems. As a long-range projecting, highly specific circuit for arousal, dysfunction of the Hcrt system leads to severe impairments. Namely, Hcrt dysfunction is implicated in two major arousal disorders: narcolepsy and insomnia. Advances in pharmacotherapy have developed promising treatments for these disorders and provide hope for improving the quality of life of individuals experiencing these frequently debilitating conditions.

A Narcolepsy

et al., 2012), and in 2014, Suvorexant (Belsomra) became the first dual hypocretin receptor antagonist approved by the FDA, which is now widely prescribed for the treatment of insomnia. As this drug has only recently been approved, there is currently insufficient evidence regarding its long-term efficacy, and future studies are necessary to determine its potential as a long-term alternative to benzodiazepines for the improvement of insomnia (Rhyne & Anderson, 2015).

V BEYOND SLEEP/WAKE

Narcolepsy is characterized by unexpected sleep episodes during times of wakefulness, excessive daytime sleepiness (EDS), and REM-like episodes that occur during wakefulness (de Lecea, 2015; Didato & Nobili, 2009; for details, see Chapter 48, this volume). Hcrt dysfunction underlies the majority of cases of this disorder (Nishino et al., 2000; Thannickal et al., 2000). Knocking out the Hcrt gene in mice results in a narcoleptic phenotype (Chemelli et al., 1999), and studies in narcoleptic dogs found mutations in the gene encoding for Hcrt-2 (Lin et al., 1999). While genetic screens of early-onset narcolepsy patients found only one case of Hcrt mutation, Hcrt deficiency is still the main cause of narcolepsy, and today, Hcrt screens are a first step in diagnosis (Didato & Nobili, 2009; Mignot et al., 2002; Nishino et al., 2000; Thannickal et al., 2000). The main treatment for this disorder is modafinil, which acts at both DAergic circuitry and Hcrt networks to maintain wakefulness (Didato & Nobili, 2009; Qu, Huang, Xu, Matsumoto, & Urade, 2008).

B Insomnia Insomnia is characterized by difficulty initiating and/ or maintaining sleep, either by disrupted sleep or early morning awakenings (Ohayon, 2002). Insomnia is thought to occur as a result of overactivity within the arousal circuitry (Riemann et al., 2015). Benzodiazepines are used as one of the major treatments for insomnia, even though they have minimal efficacy (i.e., nonsignificant decrease in sleep latencies) and considerable negative side effects, such as oversedation and next-day “hangover” effects, together with a high abuse potential (Ebert, Wafford, & Deacon, 2006; Holbrook, Crowther, Lotter, Cheng, & King, 2000). Given these issues, some Hcrt-targeting pharmacotherapies are attractive alternatives, which have begun to show promise in the clinic. Hypocretin receptor (HcrtR)-specific treatments have come up short, since HcrtR1 antagonism shows little effect on sleep, while HcrtR2 blockade minimally reduces latency to sleep and increases total amount slept (Dugovic et al., 2009, 2014). Dual HcrtR antagonists, however, show strong sleep-promoting effects (Morairty

In this section, we aim to broaden the discussion of arousal beyond sleep and wakefulness. Indeed, the Hcrt system has been implicated in motor control, stress and anxiety, and motivation. Thus, as we broaden our conceptualization of arousal, we find that the role of the Hcrts is broadened as well.

A Motor Control Little is known about how Hcrt may function to couple arousal states with motor output (Hu, Yang, Qiao, Hu, & Zhang, 2015). Hcrt deficits that underlie narcolepsy may also explain associated motor control deficits in this disorder (Burgess & Scammell, 2012; Didato & Nobili, 2009). Recent findings suggest that Hcrt projections onto the DRN may underlie these processes, since restoration of HcrtR2 in serotonergic DRN neurons of dual Hcrt receptor knockout mice suppresses cataplexy-like episodes (Hasegawa et al., 2017). Further, optogenetic stimulation of DRN terminals in the amygdala suppresses cataplexy in the Hcrt-deficient mouse model of narcolepsy (Hasegawa et al., 2017). Similarly, chemogenetic manipulations of the central amygdala have shown that this region is responsible for cataplexy in mice (Mahoney, Agostinelli, Brooks, Lowell, & Scammell, 2017). Interestingly, cataplexic episodes in narcolepsy are often triggered by strong emotions, and these findings may explain a functional circuit for this phenomenon.

B Anxiety Elevated arousal states support adaptive behavioral responses to stressful stimuli. Recent findings suggest that Hcrt may play an important role in these processes. Blockade of HcrtR1 shows anxiolytic effects across various models of anxiety. Treatment with compound 56, a HcrtR1 antagonist, reduces panic-like behaviors in animals with panic vulnerability (Bonaventure et al., 2015). Similarly, treatment with a selective HcrtR1 antagonist or a mixed HcrtR1 and HcrtR2 antagonist reduces anxiety-like behavior in a CO2 model of stress, while selective HcrtR2 antagonism does not (Johnson et al., 2015). HcrtR1 antagonism

PART B. REGULATION OF WAKING AND SLEEPING

94

6. HYPOCRETIN AND REGULATION OF SLEEP-WAKE TRANSITIONS

also reduces anxiety in a model of pain-induced anxiety (Bahaaddini, Khatamsaz, Esmaeili-Mahani, Abbasnejad, & Raoof, 2016). Together, these findings suggest an important role for HcrtR1 in the regulation of anxiety-like behavior. At the same time, Hcrt knockout mice show increased anxiety in the open field, the predator scent avoidance test, and the light-dark box test (Khalil & Fendt, 2017). Similarly, HcrtR1 KO mice show increased anxiety and startle responses (Abbas et al., 2015). Findings from these genetic studies do not negate the abovementioned pharmacological data, but instead suggest that we must use the newest behavioral and genetic techniques to characterize the role of Hcrt in anxiety. Indeed, we must acknowledge that knockout models may result in compensatory adaptations, which may influence anxiety-related behaviors. Additionally, it is important to keep in mind that the many unique behavioral paradigms used to measure anxiety differ greatly in their modalities and their resulting phenotypes, and thus, findings should be interpreted in light of the behavioral manipulations employed in these studies.

VI FUTURE DIRECTIONS The data amassed over the past 20 years have shown a critical role for Hcrt in the regulation of arousal. Modern neuroscience techniques are ushering in a new era of Hcrt research by allowing real-time, cell-specific manipulations of Hcrt circuitry. In particular, the use of optogenetics allows for precise targeting of neuronal populations with millisecond control. Recent advances in this technology have targeted additional modes of cellular physiology, allowing for more nuanced manipulations of neuronal activity. Additionally, the use of genetically encoded calcium indicators allows for the observation of real-time activity of these cells via fiber photometry and microendoscopy at a scale unachievable by conventional electrophysiological approaches. Alongside

advances in manipulation and monitoring of these circuits, progress in the quantitative modeling of Hcrt circuits must be made (Adamantidis et al., 2007; Carter et al., 2009, 2010; Jego et al., 2013; Zhang et al., 2010; Zhang, Aravanis, Adamantidis, de Lecea, & Deisseroth, 2007), as is briefly discussed in the following section.

A Quantitative Modeling of Hcrt Circuits Computational modeling of Hcrt circuits will prove particularly useful for our understanding of the following question: how do internal or external physiological states influence arousal states? Earlier models of Hcrt circuit function proposed a “flip/flop” model of activity, by which Hcrt circuit activity stabilizes wakefulness and prevents aberrant switches between mutually exclusive arousal states, such as wakefulness and sleep (Saper, Fuller, Pedersen, Lu, & Scammell, 2010). While this model provided an important, first step toward understanding and predicting the activity of this circuit, it falls short of accounting for overlapping states of arousal, such as those observed in narcolepsy and REM behavior disorder (Krueger et al., 2008; Vyazovskiy et al., 2011). The model also fails to incorporate the role of both internal and external stimuli, which may influence arousal. Indeed, these deficiencies were considered by Sorooshyari and colleagues in a model, which allowed for the hierarchical gating of information from additional neural circuits (Sorooshyari, Huerta, & de Lecea, 2015). This model is optimally designed to incorporate additional influences on arousal, such as motivational states. An alternative model has been proposed in which sleep-to-wake transitions are executed based on computations of weights (which can incorporate motivational inputs) onto an integrator neuron (Fig. 6.1). Modeling of this system will contribute greatly to our understanding of its role as an integrator and effector of arousal states.

FIG. 6.1 Integrator circuit model of sleep/ wake transitions. Weighted inputs (influenced by factors such as sleep drive and motivational states are denoted by w1, w2, w3, etc.) are fed to lateral hypothalamus (LH) hypocretin neurons (“integrators”) in real time. Integrator neurons within the LH continuously compute probabilities of wakefulness based on the functional connectivity of the system and physiological factors. Activity at this site determines the likelihood of sleep/wake transitions via its effectors at output regions. PFC, prefrontal cortex; DRN, dorsal raphe nucleus; LC, locus coeruleus; VTA, ventral tegmental area; TMN, tuberomammillary nucleus; and BF, Basal Forebrain.

PART B. REGULATION OF WAKING AND SLEEPING

REFERENCES

VII CONCLUSION Modern neuroscience techniques continue to reveal and refine the roles of neuromodulators in the regulation of behavior and arousal states. To this day, an average of 183 papers are published each year on the hypocretins and their various roles in physiology and behavior. Technical advances in the neurosciences have allowed for the ever more refined study of these circuits, with clear and direct implications for the clinic. Indeed, therapeutics targeting Hcrt circuitry have already shown promise for the treatment of narcolepsy and insomnia. We look forward to the future of the field and the advancement of Hcrt science in the lab and in the clinic.

Acknowledgments The authors would like to thank Jeremy C. Borniger for his helpful comments on the manuscript.

References Abbas, M. G., Shoji, H., Soya, S., Hondo, M., Miyakawa, T., & Sakurai, T. (2015). Comprehensive behavioral analysis of male Ox1r ( / ) mice showed implication of orexin receptor-1 in mood, anxiety, and social behavior. Frontiers in Behavioral Neuroscience, 9, 324. https://doi.org/ 10.3389/fnbeh.2015.00324. Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K., & de Lecea, L. (2007). Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature, 450(7168), 420–424. https://doi.org/10.1038/nature06310. Akiyama, M., Yuasa, T., Hayasaka, N., Horikawa, K., Sakurai, T., & Shibata, S. (2004). Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. The European Journal of Neuroscience, 20(11), 3054–3062. https://doi.org/10.1111/j.14609568.2004.03749.x. Anaclet, C., Pedersen, N. P., Ferrari, L. L., Venner, A., Bass, C. E., Arrigoni, E., et al. (2015). Basal forebrain control of wakefulness and cortical rhythms. Nature Communications, 6, 8744. https://doi. org/10.1038/ncomms9744. Aston-Jones, G., & Bloom, F. E. (1981). Activity of norepinephrinecontaining locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. The Journal of Neuroscience, 1(8), 876–886. Aston-Jones, G., & Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403–450. https:// doi.org/10.1146/annurev.neuro.28.061604.135709. Bahaaddini, M., Khatamsaz, S., Esmaeili-Mahani, S., Abbasnejad, M., & Raoof, M. (2016). The role of trigeminal nucleus caudalis orexin 1 receptor in orofacial pain-induced anxiety in rat. Neuroreport, 27(15), 1107–1113. https://doi.org/10.1097/WNR.0000000000000660. Baldo, B. A., Daniel, R. A., Berridge, C. W., & Kelley, A. E. (2003). Overlapping distributions of orexin/hypocretin- and dopaminebeta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. The Journal of Comparative Neurology, 464(2), 220–237. https://doi.org/10.1002/cne.10783. Bayer, L., Eggermann, E., Serafin, M., Saint-Mleux, B., Machard, D., Jones, B., et al. (2001). Orexins (hypocretins) directly excite

95

tuberomammillary neurons. The European Journal of Neuroscience, 14(9), 1571–1575. https://doi.org/10.1046/j.0953-816x.2001.01777.x. Bernardis, L. L., & Bellinger, L. L. (1998). The dorsomedial hypothalamic nucleus revisited: 1998 update. Proceedings of the Society for Experimental Biology and Medicine, 218, 284–306. Berridge, C. W., & Waterhouse, B. D. (2003). The locus coeruleusnoradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Research. Brain Research Reviews, 42(1), 33–84. https://doi.org/10.1016/S0165-0173(03) 00143-7. Berridge, K. C., & Robinson, T. E. (1998). What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Research. Brain Research Reviews, 28(3), 309–369. https://doi. org/10.1016/S0165-0173(98)00019-8. Bonaventure, P., Yun, S., Johnson, P. L., Shekhar, A., Fitz, S. D., Shireman, B. T., et al. (2015). A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. The Journal of Pharmacology and Experimental Therapeutics, 352(3), 590–601. https://doi.org/10.1124/jpet.114.220392. Boucetta, S., Cisse, Y., Mainville, L., Morales, M., & Jones, B. E. (2014). Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. The Journal of Neuroscience, 34(13), 4708–4727. https://doi.org/10.1523/ JNEUROSCI.2617-13.2014. Branch, A. F., Navidi, W., Tabuchi, S., Terao, A., Yamanaka, A., Scammell, T. E., et al. (2016). Progressive loss of the orexin neurons reveals dual effects on wakefulness. Sleep, 39(2), 369–377. https://doi.org/10.5665/sleep.5446. Brown, R. E., Sergeeva, O. A., Eriksson, K. S., & Haas, H. L. (2002). Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). The Journal of Neuroscience, 22(20), 8850–8859. Burgess, C. R., & Scammell, T. E. (2012). Narcolepsy: neural mechanisms of sleepiness and cataplexy. The Journal of Neuroscience, 32(36), 12305–12311. https://doi.org/10.1523/JNEUROSCI.2630-12.2012. Buzsaki, G., Bickford, R. G., Ponomareff, G., Thal, L. J., Mandel, R., & Gage, F. H. (1988). Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. The Journal of Neuroscience, 8(11), 4007–4026. Carter, M. E., Adamantidis, A., Ohtsu, H., Deisseroth, K., & de Lecea, L. (2009). Sleep homeostasis modulates hypocretin-mediated sleepto-wake transitions. The Journal of Neuroscience, 29(35), 10939–10949. https://doi.org/10.1523/JNEUROSCI.1205-09.2009. Carter, M. E., Brill, J., Bonnavion, P., Huguenard, J. R., Huerta, R., & de Lecea, L. (2012). Mechanism for hypocretin-mediated sleep-to-wake transitions. Proceedings of the National Academy of Sciences of the United States of America, 109(39), E2635–E2644. https://doi.org/10.1073/ pnas.1202526109. Carter, M. E., Yizhar, O., Chikahisa, S., Nguyen, H., Adamantidis, A., Nishino, S., et al. (2010). Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nature Neuroscience, 13(12), 1526–1533. https://doi.org/10.1038/nn.2682. Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., et al. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98(4), 437–451. https://doi.org/ 10.1016/S0092-8674(00)81973-X. Chen, A., Singh, C., Oikonomou, G., & Prober, D. A. (2017). Genetic analysis of histamine signaling in larval zebrafish sleep. eNeuro, 4(1), 1–28. https://doi.org/10.1523/ENEURO.0286-16.2017. Cho, J. R., Treweek, J. B., Robinson, J. E., Xiao, C., Bremner, L. R., Greenbaum, A., et al. (2017). Dorsal raphe dopamine neurons modulate arousal and promote wakefulness by salient stimuli. Neuron, 94(6), 1205–1219.e8. https://doi.org/10.1016/j.neuron. 2017.05.020.

PART B. REGULATION OF WAKING AND SLEEPING

96

6. HYPOCRETIN AND REGULATION OF SLEEP-WAKE TRANSITIONS

Chou, T. C., Scammell, T. E., Gooley, J. J., Gaus, S. E., Saper, C. B., & Lu, J. (2003). Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. The Journal of Neuroscience, 23(33), 10691–10702. Ciriello, J., Rosas-Arellano, M. P., Solano-Flores, L. P., & de Oliveira, C. V. R. (2003). Identification of neurons containing orexin-B (hypocretin-2) immunoreactivity in limbic structures. Brain Research, 967(1–2), 123–131. Cone, J. J., McCutcheon, J. E., & Roitman, M. F. (2014). Ghrelin acts as an interface between physiological state and phasic dopamine signaling. The Journal of Neuroscience, 34(14), 4905–4913. https:// doi.org/10.1523/JNEUROSCI.4404-13.2014. Dahan, L., Astier, B., Vautrelle, N., Urbain, N., Kocsis, B., & Chouvet, G. (2007). Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep. Neuropsychopharmacology, 32(6), 1232–1241. https://doi.org/10.1038/sj.npp.1301251. Datta, S., & Maclean, R. R. (2007). Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. Neuroscience and Biobehavioral Reviews, 31(5), 775–824. https://doi.org/10.1016/j.neubiorev.2007.02.004. de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X., Foye, P. E., Danielson, P. E., et al. (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America, 95(1), 322–327. de Lecea, L. (2015). Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Current Topics in Behavioral Neurosciences, 25, 367–378. https://doi.org/10.1007/7854-2014-364. de Lecea, L., & Sutcliffe, J. G. (2005). The hypocretins and sleep. The FEBS Journal, 272(22), 5675–5688. https://doi.org/10.1111/j.17424658.2005.04981.x. De Sarro, G. B., Ascioti, C., Froio, F., Libri, V., & Nisticò, G. (1987). Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms. British Journal of Pharmacology, 90(4), 675–685. Diano, S., Horvath, B., Urbanski, H. F., Sotonyi, P., & Horvath, T. L. (2003). Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets. Endocrinology, 144(9), 3774–3778. https://doi.org/10.1210/en.2003-0274. Didato, G., & Nobili, L. (2009). Treatment of narcolepsy. Expert Review of Neurotherapeutics, 9(6), 897–910. https://doi.org/10.1586/ ern.09.29. Dube, M. G., Kalra, S. P., & Kalra, P. S. (1999). Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. 1This study was presented in part at the 28th Annual Meeting of the Society for Neuroscience, Los Angeles, CA, in November 1998.1. Brain Research, 842(2), 473–477. https://doi.org/10.1016/S0006-8993(99)01824-7. Dugovic, C., Shelton, J. E., Aluisio, L. E., Fraser, I. C., Jiang, X., Sutton, S. W., et al. (2009). Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. The Journal of Pharmacology and Experimental Therapeutics, 330(1), 142–151. https://doi.org/10.1124/jpet.109.152009. Dugovic, C., Shelton, J. E., Yun, S., Bonaventure, P., Shireman, B. T., & Lovenberg, T. W. (2014). Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism. Frontiers in Neuroscience, 8, 28. https://doi.org/10.3389/fnins. 2014.00028. Duque, A., Balatoni, B., Detari, L., & Zaborszky, L. (2000). EEG correlation of the discharge properties of identified neurons in the basal forebrain. Journal of Neurophysiology, 84(3), 1627–1635. https://doi.org/10.1152/jn.2000.84.3.1627. Eban-Rothschild, A., Rothschild, G., Giardino, W. J., Jones, J. R., & de Lecea, L. (2016). VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nature Neuroscience, 19(10), 1356–1366. https://doi.org/10.1038/nn.4377.

Ebert, B., Wafford, K. A., & Deacon, S. (2006). Treating insomnia: current and investigational pharmacological approaches. Pharmacology & Therapeutics, 112(3), 612–629. https://doi.org/ 10.1016/j.pharmthera.2005.04.014. Eggermann, E., Serafin, M., Bayer, L., Machard, D., Saint-Mleux, B., Jones, B. E., et al. (2001). Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience, 108(2), 177–181. Eriksson, K. S., Sergeeva, O., Brown, R. E., & Haas, H. L. (2001). Orexin/ hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. The Journal of Neuroscience, 21(23), 9273–9279. https://doi.org/ 10.1523/JNEUROSCI.21-23-09273.2001. España, R. A., Baldo, B. A., Kelley, A. E., & Berridge, C. W. (2001). Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience, 106(4), 699–715. España, R. A., Melchior, J. R., Roberts, D. C. S., & Jones, S. R. (2011). Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine selfadministration. Psychopharmacology, 214(2), 415–426. https://doi.org/ 10.1007/s00213-010-2048-8. Fadel, J., & Deutch, A. Y. (2002). Anatomical substrates of orexindopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience, 111(2), 379–387. Fujita, A., Bonnavion, P., Wilson, M. H., Mickelsen, L. E., Bloit, J., de Lecea, L., et al. (2017). Hypothalamic tuberomammillary nucleus neurons: electrophysiological diversity and essential role in arousal stability. The Journal of Neuroscience, 37(39), 9574–9592. https://doi.org/10.1523/JNEUROSCI.0580-17.2017. Fuller, P. M., Sherman, D., Pedersen, N. P., Saper, C. B., & Lu, J. (2011). Reassessment of the structural basis of the ascending arousal system. The Journal of Comparative Neurology, 519(5), 933–956. https://doi. org/10.1002/cne.22559. Gompf, H. S., & Aston-Jones, G. (2008). Role of orexin input in the diurnal rhythm of locus coeruleus impulse activity. Brain Research, 1224, 43–52. https://doi.org/10.1016/j.brainres.2008.05.060. Haas, H., & Panula, P. (2003). The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Reviews Neuroscience, 4(2), 121–130. https://doi.org/10.1038/nrn1034. Hagan, J. J., Leslie, R. A., Patel, S., Evans, M. L., Wattam, T. A., Holmes, S., et al. (1999). Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proceedings of the National Academy of Sciences of the United States of America, 96(19), 10911–10916. Han, Y., Shi, Y., Xi, W., Zhou, R., Tan, Z., Wang, H., et al. (2014). Selective activation of cholinergic basal forebrain neurons induces immediate sleep-wake transitions. Current Biology, 24(6), 693–698. https://doi.org/10.1016/j.cub.2014.02.011. Hassani, O. K., Lee, M. G., & Jones, B. E. (2009). Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep-wake cycle. Proceedings of the National Academy of Sciences of the United States of America, 106(7), 2418–2422. https:// doi.org/10.1073/pnas.0811400106. Hasegawa, E., Maejima, T., Yoshida, T., Masseck, O. A., Herlitze, S., Yoshioka, M., et al. (2017). Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity. Proceedings of the National Academy of Sciences of the United States of America, 114(17), E3526–E3535. https://doi.org/ 10.1073/pnas.1614552114. Hernández Peón, R., & Chávez Ibarra, G. (1963). Sleep induced by electrical or chemical stimulation of the forebrain. Electroencephalography and Clinical Neurophysiology, 24, 188. Hobson, J. A., McCarley, R. W., & Wyzinski, P. W. (1975). Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science, 189(4196), 55–58. Holbrook, A. M., Crowther, R., Lotter, A., Cheng, C., & King, D. (2000). Meta-analysis of benzodiazepine use in the treatment of insomnia. Canadian Medical Association Journal, 162(2), 225–233. Horvath, T. L., Peyron, C., Diano, S., Ivanov, A., Aston-Jones, G., Kilduff, T. S., et al. (1999). Hypocretin (orexin) activation and

PART B. REGULATION OF WAKING AND SLEEPING

REFERENCES

synaptic innervation of the locus coeruleus noradrenergic system. The Journal of Comparative Neurology, 415(2), 145–159. https://doi. org/10.1002/(SICI)1096-9861(19991213)415:2<145::AID-CNE1>3.0. CO;2-2. Hu, B., Yang, N., Qiao, Q. -C., Hu, Z. -A., & Zhang, J. (2015). Roles of the orexin system in central motor control. Neuroscience and Biobehavioral Reviews, 49, 43–54. https://doi.org/10.1016/j.neubiorev. 2014.12.005. Huang, Z. L., Qu, W. M., Li, W. D., Mochizuki, T., Eguchi, N., Watanabe, T., et al. (2001). Arousal effect of orexin A depends on activation of the histaminergic system. Proceedings of the National Academy of Sciences of the United States of America, 98(17), 9965–9970. https://doi.org/10.1073/pnas.181330998. Irmak, S. O., & de Lecea, L. (2014). Basal forebrain cholinergic modulation of sleep transitions. Sleep, 37(12), 1941–1951. https:// doi.org/10.5665/sleep.4246. Ishibashi, M., Gumenchuk, I., Kang, B., Steger, C., Lynn, E., Molina, N. E., et al. (2015). Orexin receptor activation generates gamma band input to cholinergic and serotonergic arousal system neurons and drives an intrinsic Ca(2+)-dependent resonance in LDT and PPT cholinergic neurons. Frontiers in Neurology, 6, 120. https://doi.org/ 10.3389/fneur.2015.00120. Ishibashi, M., Gumenchuk, I., Miyazaki, K., Inoue, T., Ross, W. N., & Leonard, C. S. (2016). Hypocretin/orexin peptides alter spike encoding by serotonergic dorsal raphe neurons through two distinct mechanisms that increase the late afterhyperpolarization. The Journal of Neuroscience, 36(39), 10097–10115. https://doi.org/ 10.1523/JNEUROSCI.0635-16.2016. Jego, S., Glasgow, S. D., Herrera, C. G., Ekstrand, M., Reed, S. J., Boyce, R., et al. (2013). Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nature Neuroscience, 16(11), 1637–1643. https://doi.org/10.1038/nn.3522. Johnson, P. L., Federici, L. M., Fitz, S. D., Renger, J. J., Shireman, B., Winrow, C. J., et al. (2015). Orexin 1 and 2 receptor involvement in Co2-induced panic-associated behavior and autonomic responses. Depression and Anxiety, 32(9), 671–683. https://doi.org/ 10.1002/da.22403. Jones, B. E. (2017). Principal cell types of sleep-wake regulatory circuits. Current Opinion in Neurobiology, 44, 101–109. https://doi.org/ 10.1016/j.conb.2017.03.018. Kaitin, K. I. (1984). Preoptic area unit activity during sleep and wakefulness in the cat. Experimental Neurology, 83(2), 347–357. https://doi.org/10.1016/S0014-4886(84)90103-1. Khalil, R., & Fendt, M. (2017). Increased anxiety but normal fear and safety learning in orexin-deficient mice. Behavioural Brain Research, 320, 210–218. https://doi.org/10.1016/j.bbr.2016.12.007. Kim, T., Thankachan, S., McKenna, J. T., McNally, J. M., Yang, C., Choi, J. H., et al. (2015). Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proceedings of the National Academy of Sciences of the United States of America, 112(11), 3535–3540. https://doi.org/10.1073/ pnas.1413625112. Kohlmeier, K. A., Watanabe, S., Tyler, C. J., Burlet, S., & Leonard, C. S. (2008). Dual orexin actions on dorsal raphe and laterodorsal tegmentum neurons: noisy cation current activation and selective enhancement of Ca2+ transients mediated by L-type calcium channels. Journal of Neurophysiology, 100(4), 2265–2281. https://doi. org/10.1152/jn.01388.2007. Kohlmeier, K. A., Inoue, T., & Leonard, C. S. (2004). Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. Journal of Neurophysiology, 92(1), 221–235. https://doi. org/10.1152/jn.00076.2004. Korotkova, T. M., Sergeeva, O. A., Eriksson, K. S., Haas, H. L., & Brown, R. E. (2003). Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. The Journal of Neuroscience, 23(1), 7–11.

97

Koyama, Y., & Hayaishi, O. (1994). Firing of neurons in the preoptic/anterior hypothalamic areas in rat: its possible involvement in slow wave sleep and paradoxical sleep. Neuroscience Research, 19(1), 31–38. https://doi.org/10.1016/01680102(94)90005-1. Krueger, J. M., Rector, D. M., Roy, S., Van Dongen, H. P. A., Belenky, G., & Panksepp, J. (2008). Sleep as a fundamental property of neuronal assemblies. Nature Reviews Neuroscience, 9(12), 910–919. https://doi.org/10.1038/nrn2521. Lee, M. G., Hassani, O. K., Alonso, A., & Jones, B. E. (2005). Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. The Journal of Neuroscience, 25(17), 4365–4369. https://doi.org/10.1523/JNEUROSCI.0178-05.2005. Lee, M. G., Hassani, O. K., & Jones, B. E. (2005). Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. The Journal of Neuroscience, 25(28), 6716–6720. https://doi. org/10.1523/JNEUROSCI.1887-05.2005. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., et al. (1999). The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98(3), 365–376. https://doi. org/10.1016/S0092-8674(00)81965-0. Lu, J., Greco, M. A., Shiromani, P., & Saper, C. B. (2000). Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. The Journal of Neuroscience, 20(10), 3830–3842. Mahler, S. V., Moorman, D. E., Smith, R. J., James, M. H., & AstonJones, G. (2014). Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nature Neuroscience, 17(10), 1298–1303. https://doi.org/10.1038/nn.3810. Mahoney, C. E., Agostinelli, L. J., Brooks, J. N. K., Lowell, B. B., & Scammell, T. E. (2017). GABAergic neurons of the central amygdala promote cataplexy. The Journal of Neuroscience, 37(15), 3995–4006. https://doi.org/10.1523/JNEUROSCI.4065-15.2017. McGinty, D. J., & Harper, R. M. (1976). Dorsal raphe neurons: depression of firing during sleep in cats. Brain Research, 101(3), 569–575. https://doi.org/10.1016/0006-8993(76)90480-7. Mignot, E., Lammers, G. J., Ripley, B., Okun, M., Nevsimalova, S., Overeem, S., et al. (2002). The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Archives of Neurology, 59(10), 1553–1562. https:// doi.org/10.1001/archneur.59.10.1553. Mileykovskiy, B. Y., Kiyashchenko, L. I., & Siegel, J. M. (2005). Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron, 46(5), 787–798. https://doi.org/10.1016/j.neuron. 2005.04.035. Mintz, E. M., van den Pol, A. N., Casano, A. A., & Albers, H. E. (2001). Distribution of hypocretin-(orexin) immunoreactivity in the central nervous system of Syrian hamsters (Mesocricetus auratus). Journal of Chemical Neuroanatomy, 21(3), 225–238. https://doi.org/ 10.1016/S0891-0618(01)00111-9. Morairty, S. R., Revel, F. G., Malherbe, P., Moreau, J. -L., Valladao, D., Wettstein, J. G., et al. (2012). Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS One, 7(7), e39131, https://doi.org/10.1371/ journal.pone.0039131. Moriya, R., Kanamaru, M., Ookuma, N., Tanaka, K. F., Izumizaki, M., Onimaru, H., et al. (2017). The effect of activating serotonergic neurons in the dorsal raphe nucleus on control of vigilance state. Vol. 50. Sleep and control of breathing (p. OA1753). European Respiratory Society. https://doi.org/10.1183/1393003.congress2017.OA1753. Mullett, M. A., Billington, C. J., Levine, A. S., & Kotz, C. M. (2000). Hypocretin I in the lateral hypothalamus activates key feedingregulatory brain sites. NeuroReport, 11(1), 103–108. Nakamura, T., Uramura, K., Nambu, T., Yada, T., Goto, K., Yanagisawa, M., et al. (2000). Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Research, 873(1), 181–187.

PART B. REGULATION OF WAKING AND SLEEPING

98

6. HYPOCRETIN AND REGULATION OF SLEEP-WAKE TRANSITIONS

Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M., & Goto, K. (1999). Distribution of orexin neurons in the adult rat brain. Brain Research, 827(1–2), 243–260. Narita, M., Nagumo, Y., Hashimoto, S., Narita, M., Khotib, J., Miyatake, M., et al. (2006). Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. The Journal of Neuroscience, 26(2), 398–405. https://doi.org/10.1523/JNEUROSCI.2761-05.2006. Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., & Mignot, E. (2000). Hypocretin (orexin) deficiency in human narcolepsy. The Lancet, 355(9197), 39–40. https://doi.org/10.1016/S0140-6736(99)05582-8. Ohayon, M. M. (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews, 6(2), 97–111. https://doi.org/10.1053/smrv.2002.0186. Ohno, K., Hondo, M., & Sakurai, T. (2008). Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice. Journal of Pharmacological Sciences, 106(3), 485–491. https:// doi.org/10.1254/jphs.FP0071986. Oishi, Y., Suzuki, Y., Takahashi, K., Yonezawa, T., Kanda, T., Takata, Y., et al. (2017). Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D2-like receptors in mice. Brain Structure & Function, 222(6), 2907–2915. https://doi.org/ 10.1007/s00429-017-1365-7. Oleson, E. B., Gentry, R. N., Chioma, V. C., & Cheer, J. F. (2012). Subsecond dopamine release in the nucleus accumbens predicts conditioned punishment and its successful avoidance. The Journal of Neuroscience, 32(42), 14804–14808. https://doi.org/10.1523/ JNEUROSCI.3087-12.2012. Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., et al. (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Medicine, 6(9), 991–997. https://doi.org/ 10.1038/79690. Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., et al. (1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems. The Journal of Neuroscience, 18(23), 9996–10015. Qu, W. -M., Huang, Z. -L., Xu, X. -H., Matsumoto, N., & Urade, Y. (2008). Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. The Journal of Neuroscience, 28(34), 8462–8469. https://doi.org/10.1523/JNEUROSCI.1819-08.2008. Rasmussen, K., Morilak, D. A., & Jacobs, B. L. (1986). Single unit activity of locus coeruleus neurons in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli. Brain Research, 371(2), 324–334. Rhyne, D. N., & Anderson, S. L. (2015). Suvorexant in insomnia: efficacy, safety and place in therapy. Therapeutic Advances in Drug Safety, 6(5), 189–195. https://doi.org/10.1177/2042098615595359. Riemann, D., Nissen, C., Palagini, L., Otte, A., Perlis, M. L., & Spiegelhalder, K. (2015). The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurology, 14(5), 547–558. https://doi.org/10.1016/S1474-4422(15)00021-6. Sahu, A., & Kalra, S. P. (1993). Neuropeptidergic regulation of feeding behavior. Trends in Endocrinology & Metabolism, 4(7), 217–224. https://doi.org/10.1016/1043-2760(93)90125-X. Saito, Y. C., Tsujino, N., Hasegawa, E., Akashi, K., Abe, M., Mieda, M., et al. (2013). GABAergic neurons in the preoptic area send direct inhibitory projections to orexin neurons. Frontiers in Neural Circuits, 7, 192. https://doi.org/10.3389/fncir.2013.00192. Sakai, K. (2015). Paradoxical (rapid eye movement) sleep-on neurons in the laterodorsal pontine tegmentum in mice. Neuroscience, 310, 455–471. https://doi.org/10.1016/j.neuroscience.2015.09.063. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., et al. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92(4), 573–585. https://doi.org/ 10.1016/S0092-8674(00)80949-6.

Sakurai, T., Nagata, R., Yamanaka, A., Kawamura, H., Tsujino, N., Muraki, Y., et al. (2005). Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron, 46(2), 297–308. https://doi.org/10.1016/j.neuron.2005.03.010. Saper, C. B., & Fuller, P. M. (2017). Wake-sleep circuitry: an overview. Current Opinion in Neurobiology, 44, 186–192. https://doi.org/ 10.1016/j.conb.2017.03.021. Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J., & Scammell, T. E. (2010). Sleep state switching. Neuron, 68(6), 1023–1042. https://doi. org/10.1016/j.neuron.2010.11.032. Sasaki, K., Suzuki, M., Mieda, M., Tsujino, N., Roth, B., & Sakurai, T. (2011). Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice. PLoS One, 6(5), e20360. https:// doi.org/10.1371/journal.pone.0020360. Schultz, W. (1998). Predictive reward signal of dopamine neurons. Journal of Neurophysiology, 80(1), 1–27. https://doi.org/10.1152/jn.1998.80.1.1. Schwartz, M. D., & Kilduff, T. S. (2015). The neurobiology of sleep and wakefulness. The Psychiatric Clinics of North America, 38(4), 615–644. https://doi.org/10.1016/j.psc.2015.07.002. Sheng, Z., Santiago, A. M., Thomas, M. P., & Routh, V. H. (2014). Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Molecular and Cellular Neurosciences, 62, 30–41. https://doi.org/ 10.1016/j.mcn.2014.08.001. Sorooshyari, S., Huerta, R., & de Lecea, L. (2015). A framework for quantitative modeling of neural circuits involved in sleep-to-wake transition. Frontiers in Neurology, 6, 32. https://doi.org/10.3389/ fneur.2015.00032. Sterman, M. B., & Clemente, C. D. (1962). Forebrain inhibitory mechanisms: sleep patterns induced by basal forebrain stimulation in the behaving cat. Experimental Neurology, 6, 103–117. https:// doi.org/10.1016/0014-4886(62)90081-X. Takahashi, K., Lin, J. S., & Sakai, K. (2008). Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience, 153(3), 860–870. https://doi.org/ 10.1016/j.neuroscience.2008.02.058. Takahashi, K., Koyama, Y., Kayama, Y., & Yamamoto, M. (2002). Effects of orexin on the laterodorsal tegmental neurones. Psychiatry and Clinical Neurosciences, 56(3), 335–336. https://doi.org/10.1046/ j.1440-1819.2002.00967.x. Takahashi, K., Lin, J. -S., & Sakai, K. (2006). Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse. The Journal of Neuroscience, 26(40), 10292–10298. https://doi.org/10.1523/JNEUROSCI.2341-06.2006. Taylor, N. E., Van Dort, C. J., Kenny, J. D., Pei, J., Guidera, J. A., Vlasov, K. Y., et al. (2016). Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia. Proceedings of the National Academy of Sciences of the United States of America, 113, 12826–12831. https://doi.org/ 10.1073/pnas.1614340113. Thakkar, M., Portas, C., & McCarley, R. W. (1996). Chronic lowamplitude electrical stimulation of the laterodorsal tegmental nucleus of freely moving cats increases REM sleep. Brain Research, 723(1–2), 223–227. https://doi.org/10.1016/0006-8993(96)00256-9. Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27(3), 469–474. https://doi.org/10.1016/S0896-6273(00)00058-1. Torterolo, P., Sampogna, S., Morales, F. R., & Chase, M. H. (2006). MCHcontaining neurons in the hypothalamus of the cat: searching for a role in the control of sleep and wakefulness. Brain Research, 1119(1), 101–114. https://doi.org/10.1016/j.brainres.2006.08.100. Tsunematsu, T., Tabuchi, S., Tanaka, K. F., Boyden, E. S., Tominaga, M., & Yamanaka, A. (2013). Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice. Behavioural Brain Research, 255, 64–74. https://doi.org/10.1016/ j.bbr.2013.05.021.

PART B. REGULATION OF WAKING AND SLEEPING

REFERENCES

Tung, L. -W., Lu, G. -L., Lee, Y. -H., Yu, L., Lee, H. -J., Leishman, E., et al. (2016). Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nature Communications, 7, 12199. https://doi.org/10.1038/ ncomms12199. Uschakov, A., Gong, H., McGinty, D., & Szymusiak, R. (2007). Efferent projections from the median preoptic nucleus to sleepand arousal-regulatory nuclei in the rat brain. Neuroscience, 150(1), 104–120. https://doi.org/10.1016/j.neuroscience.2007.05.055. Vandermaelen, C. P., & Aghajanian, G. K. (1983). Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. Brain Research, 289(1–2), 109–119. Vittoz, N. M., & Berridge, C. W. (2006). Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology, 31(2), 384–395. https://doi.org/10.1038/sj.npp.1300807. Vyazovskiy, V. V., Olcese, U., Hanlon, E. C., Nir, Y., Cirelli, C., & Tononi, G. (2011). Local sleep in awake rats. Nature, 472(7344), 443–447. https://doi.org/10.1038/nature10009. Xi, M. C., Morales, F. R., & Chase, M. H. (2001). Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Research, 901(1–2), 259–264. https://doi.org/10.1016/S0006-8993(01)02317-4.

99

Xie, X., Crowder, T. L., Yamanaka, A., Morairty, S. R., Lewinter, R. D., Sakurai, T., et al. (2006). GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. The Journal of Physiology, 574(Pt. 2), 399–414. https://doi.org/10.1113/ jphysiol.2006.108266. Xu, M., Chung, S., Zhang, S., Zhong, P., Ma, C., Chang, W. -C., et al. (2015). Basal forebrain circuit for sleep-wake control. Nature Neuroscience, 18(11), 1641–1647. https://doi.org/10.1038/nn.4143. Yoshida, K., McCormack, S., España, R. A., Crocker, A., & Scammell, T. E. (2006). Afferents to the orexin neurons of the rat brain. The Journal of Comparative Neurology, 494(5), 845–861. https://doi.org/ 10.1002/cne.20859. Zhang, F., Aravanis, A. M., Adamantidis, A., de Lecea, L., & Deisseroth, K. (2007). Circuit-breakers: optical technologies for probing neural signals and systems. Nature Reviews Neuroscience, 8(8), 577–581. https://doi.org/10.1038/nrn2192. Zhang, F., Gradinaru, V., Adamantidis, A. R., Durand, R., Airan, R. D., de Lecea, L., et al. (2010). Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nature Protocols, 5(3), 439–456. https://doi.org/10.1038/nprot.2009.226.

PART B. REGULATION OF WAKING AND SLEEPING