How do the basal ganglia regulate sleep–wake behavior?

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How do the basal ganglia regulate sleep–wake behavior? Michael Lazarus1, Zhi-Li Huang1,2, Jun Lu3, Yoshihiro Urade1, and Jiang-Fan Chen4 1

Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan Department of Pharmacology, Fudan University Shanghai Medical College, 138 Yixueyuan Road, Shanghai 200032, China 3 Division of Sleep Medicine and Program in Neuroscience, Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 4 Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA 2

The basal ganglia (BG) are involved in motor function, habit formation, and reward or addictive behaviors, but the question as to how the BG integrate arousal with these fundamental striatal functions has only recently received much attention. Findings based on electrophysiology, neurotoxic lesioning, and the use of transgenic animals have established that the striatum and globus pallidus are key structural elements for the control of sleep and wakefulness. Here, we discuss emerging anatomical and molecular mechanisms of sleep–wake regulation at work in the BG. Furthermore, we propose a model whereby adenosine and dopamine receptors in the nucleus accumbens (NAc) are involved in the integration of behavioral processes and the induction of wakefulness through cortical activation. Introduction The BG are involved in numerous neurobiological processes including motor function, habit learning or formation, reinforcement, and addictive behaviors. The BG are the largest structures in the forebrain and consist of four major nuclei, the striatum, globus pallidus (GP), subthalamic nucleus (STN), and substantia nigra (SN) [1], and are strongly connected to the cortex, thalamus, and amygdala, as well as midbrain dopaminergic neurons. Thus, BG act as a cohesive functional unit in optimizing behavior and regulating the vigilance state of wakefulness. However, the specific role of the two efferent pathways of the BG, striatonigral versus striatopallidal, in integrating wakefulness, motor function, and behavior has received surprisingly little attention. Adenosine promotes sleep through the activation of adenosine A1 and A2A receptors (see Glossary) [2,3]. A2A receptors are densely expressed on striatopallidal neurons of the BG, where dopamine D2 receptors are co-expressed with A2A receptors, in contrast to dopamine D1 receptors, which are colocalized with A1 receptors on striatonigral neurons. Whereas the mesolimbic dopamine system from the midbrain to the striatum for motor control and motivational behavior has been studied by many laboratories for decades (Box 1), experimental evidence of the intrinsic

Corresponding authors: Urade, Y. ([email protected]); Chen, J-F. ([email protected]). Keywords: direct pathway; indirect pathway; locomotion; movement disorders; sleep; adenosine

roles of adenosine and dopamine in the BG for sleep–wake regulation has only recently started to emerge. Recent studies have revealed that caffeine, an antagonist to A1 and A2A receptors, induces strong wakefulness by blocking the action of adenosine on A2A receptors and that the arousal effect of caffeine depends on A2A receptors in the shell of the NAc, but not other areas within or outside of the BG [4,5]. Here we discuss evolving anatomical and molecular mechanistic models of sleep–wake regulation in the BG and propose that the NAc is a key node between the traditional pathways for locomotion and motivational behaviors [6] and the circuitry for sleep [7,8]. Recent findings that the dorsal striatum, NAc, and GP are key structural elements for the regulation of wakeful consciousness have a major impact on our understanding of where and how A2A receptor antagonists or D2 receptor agonists [most commonly used for treatment of Parkinson’s disease (PD)], affect sleep and wakefulness.

Glossary Adenosine receptors: group of purinergic, G-protein-coupled receptors of which four receptor subtypes are known: A1 and A3 receptors are coupled to Gi/Go proteins, which inhibit adenylyl cyclase. Adenylyl cyclase inhibition results in a decrease in intracellular cAMP, activation of phospholipase C and several types of inwardly rectifying potassium channels, and inactivation of voltage-gated calcium channels. A2A and A2B receptors are coupled to Gs proteins, which stimulate adenylyl cyclase and induce the synthesis of cAMP. Dopamine receptors: there are five dopamine receptor subtypes, which can be categorized as either D1-like (D1 and D5) or D2-like (D2–D4) receptors. D1 and D5 receptors are coupled to Gs and stimulate adenylyl cyclase, whereas D2, D3, and D4 receptors are coupled to Gi/Go and inhibit adenylyl cyclase, activate inwardly rectifying potassium channels, and inhibit voltage-gated calcium channels. Polysomnography: multi-parametric electrical test used to study sleep qualitatively and quantitatively and as a diagnostic tool in sleep medicine. Sleep–wake patterns are assessed by examining the electroencephalogram (EEG), which records spontaneous electrical activity in the brain, and the electrooculogram (which records eye movements) and the electromyogram (which records muscle tension). Rapid eye movement (REM) or paradoxical sleep: sleep consists of two fundamentally different stages: REM and non-REM (NREM) sleep. REM sleep is characterized by rapid low-voltage EEG, random eye movement, and muscle atonia (i.e. a state in which motor neurons are not stimulated). REM sleep is occasionally called paradoxical sleep, because the body appears to be in deep sleep but brain activity resembles that of wakefulness. Slow-wave or NREM sleep: unlike REM sleep, there is no eye movement during this stage and muscles are not paralyzed. Human NREM sleep can be subdivided into three stages, of which stage 3 is called slow-wave sleep or deep sleep and is characterized by large, slow delta brain waves (0.5–4 Hz) in the EEG.

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Box 1. Structure and function of the striatum The striatum is the primary input nucleus of the BG and can be subdivided into the dorsolateral, dorsomedial, and ventral striatum. Whereas the dorsal striatum in primates can be anatomically subdivided into the medially located caudate nucleus and the laterally positioned putamen, no clear division is possible in rodents between dorsolateral and dorsomedial parts of the striatum. The dorsal striatum receives glutamatergic inputs from the neocortex and thalamus, and also has dopaminergic afferents from the SN in the midbrain (Figure I). The ventral striatum is commonly associated with the NAc, which can be anatomically subdivided into core and shell regions. The shell-associated neural network has a closer functional relation to the amygdala than to the dorsal striatum, to which the NAc core shows more similarity [91]. Like the dorsal striatum, the NAc receives glutamatergic inputs from the frontal cortex, but is also considered as a gateway for limbic structures and has distinct dopaminergic innervation from the VTA, a midbrain nucleus adjacent to the SN [92]. The vast majority of neurons in the striatum contain GABA as their inhibitory neurotransmitter, including all MSNs and a small number (<5%) of medium-sized aspiny interneurons [93]. In addition, a small population of giant cholinergic interneurons can be found in the striatum [94]. MSNs are functionally classified according to their gene expression and axonal projections as striatonigral or striatopallidal

[95,96]. D1 receptor-positive striatonigral MSNs project to the medial GP and SN pars reticulata and coexpress D1 receptors and substance P; D2 receptor striatopallidal MSNs project to the lateral GP and coexpress D2 and A2A receptors and enkephalin. According to a classical model of the control of movement, BG are commonly categorized into direct and indirect pathways, which originate from striatonigral and striatopallidal MSNs, respectively [97–99] and are differentially modulated by dopamine through its action on excitatory D1 receptors (direct pathway) or inhibitory D2 receptors (indirect pathway) [100]. Although dopamine has opposite effects on activities of the direct and indirect pathways, it enhances motor function in both cases. Dysfunction of the striatum leads to devastating motor disorders, including PD, highlighting the central function of the BG in the control of movement [1]. In addition, the dorsal striatum has been implicated in procedural or implicit learning to establish automatized responses or habits and to influence cognitive behavior [84–86]. The ventral striatum has a key role in motivation and in reinforcement through rewards and punishment, and abnormal activity in the ventral striatum contributes to addictive behaviors [6,87,88]. There is also mounting evidence that different parts of the BG are involved in a wide range of neuropsychiatric disorders, such as schizophrenia, depression, and Tourette syndrome [101,102].

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Figure I. Schematic representation of the main projections leading to and from the striatum. The striatum consists of the nucleus accumbens (NAc), olfactory tubercle (OT) and caudate-putamen (CPu). The main function of the striatum is planning and control of movement. The dorsal striatum (i.e. the CPu) is generally associated with modulation of movement, whereas findings for local depletion of dopamine and administration of dopamine-related drugs indicate that the ventral striatum (i.e. the NAc and OT) is more involved in initiation of locomotion [81–83]. Structural elements of the striatum have behavioral functions that range from procedural learning and habit formation [84–86] in the CPu to processing of motivational and reward and reinforcement behaviors in the NAc [6,87,88] and sensory and cocaine reward events in the OT [83,89,90]. The striatum receives glutamatergic (black), dopaminergic (blue), and adenosinergic (red) inputs from many brain areas, but it should be noted that the neural source of adenosine in the striatum remains a mystery. All output neurons of the striatum use GABA (magenta round-headed lines) as neurotransmitter and have inhibitory effects on their targets. Abbreviations: A1R, A1 receptor; A2AR, A2A receptor; AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid receptor; D1R, D1 receptor; D2R, D2 receptor; GP, globus pallidus; LHA, lateral hypothalamus; mPFC, medial prefrontal cortex; NMDAR, N-methyl-D-aspartate receptor; PB, parabrachial nucleus; SLEA, sublenticular extended amygdala; SN, substantia nigra; VTA, ventral tegmental area.

Distinct roles of the four major nuclei of the BG in the sleep–wake cycle: evidence from eletrophysiological recordings and anatomical lesioning Electrophysiological studies Although the pattern of BG neuron activity has been studied extensively by means of electrophysiological 724

recordings, only a few laboratories have tried to characterize neuronal firing during sleep–wake states in alert animals. Available studies indicate that firing patterns are distinct in different nuclei of the BG. The activity of medium spiny neurons (MSNs) during wakefulness is characterized by irregular firing patterns with temporally

Lesion studies Studies involving neurotoxic lesioning of the BG indicate a significant causal role between BG structures and regulation of the sleep–wake cycle. Bilateral lesions made in the striatum result in a significant reduction in time spent in wakefulness, as well as fragmentation of both sleep and wakefulness. However, when the striatal lesions include the NAc, their effect on wakefulness is attenuated [14]. Consistent with this observation, lesions restricted to the NAc produce an increase in wakefulness and a reduced duration of bouts of non-REM (NREM) sleep. These findings suggest that the dorsal and ventral striatum play opposing roles in sleep–wake regulation: the caudate–putamen (CPu) enhances wakefulness whereas the NAc promotes sleep. Cell body-specific lesioning of the external GP (GPe) leads to insomnia in rats [14]. Specifically, a dramatic increase (45%) in total wakefulness and pronounced fragmentation of NREM sleep and wakefulness, including more sleep transitions and shortened sleep bouts, were observed [14]. Moreover, loss of neurons in the SN, but not the internal GP or STN, affected sleep–wake behavior towards an increase in wakefulness [14,15]. Such findings suggest that loss of dopaminergic input from the SN to the dorsal striatum in PD may contribute, at least in part, to the insomnia observed in these patients [16]. Interestingly, lesions in the CPu, NAc, and GP lead to a generalized slowing of the cortical electroencephalogram (EEG), with less theta and more delta power during wakefulness and REM and NREM sleep [14], a phenomenon that is also observed in PD patients [17]. The GPe contains direct cortical-projecting neurons, and therefore it has been hypothesized that a dorsostriato–pallido–cortical loop is a likely mechanism by which the dorsal striatum and the GPe contribute to sleep–wake behavior (Figure 1) [18]. The model predicts that GABAergic GPe neurons suppress cortical activity – regardless of the sleep–wake state – by modulating activity of layer V pyramidal neurons and interneurons in the cerebral cortex. Disinhibition by loss of GPe neurons (e.g. neurotoxic lesioning) or dopamine input (e.g. in PD patients) may therefore lead to cortical activity, as occurs in wakefulness.

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disorganized depolarizing events, whereas during slow– wave sleep MSNs show brisk neuronal firing resulting from rhythmic membrane-potential fluctuations between a hyperpolarized quiescent state and a depolarized state [9]. By contrast, single unit recordings of GP neurons show that activity patterns vary across the sleep–wake cycle, with GP neurons being most active during wakefulness and rapid eye movement (REM) sleep (i.e. they fire faster during wakefulness and REM sleep than during slow-wave sleep) [10]. Recording of neuronal activity for dopaminergic neurons of the SN and ventral tegmental area (VTA) in freely moving cats initially established that these cells do not change their mean firing rate across the sleep–wake cycle [11,12], leading to the traditional wisdom that dopamine is the only monoaminergic neurotransmitter not involved in sleep physiology. This view, however, is challenged by recent findings. One such study, using unit recordings in unanesthetized head-restrained rats, demonstrated that dopaminergic neurons of the VTA show prominent burst firing during REM sleep [13].

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Figure 1. Model in which a dorsostriato–pallido–cortical loop regulates sleep– wake behavior and cortical activation. The caudate–putamen (CPu) projects to the external globus pallidus (GPe), which in turn projects directly or via the thalamus (mainly the mediodorsal thalamic nucleus) to the cerebral cortex. Therefore, activity of layer V pyramidal neurons and interneurons in the cerebral cortex is modulated through inhibition by GABAergic GPe neurons [14,18]. Disinhibition of the cerebral cortex by inhibition (e.g. loss of dopamine input to the CPu) or neurotoxic lesioning of GPe neurons may therefore lead to cortical activity, as occurs in wakefulness. Black arrows represent excitatory glutamatergic synapses; magenta round-headed lines represent inhibitory GABAergic synapses.

Critical role of the dopaminergic system in the BG for the sleep–wake cycle Researchers have long attempted to elucidate the role of dopamine in the regulation of sleep and wakefulness. Seminal findings based on electrolytic lesioning of neurons in the midbrain of cats, which showed that dopaminecontaining neurons of the SN and VTA are involved in only the maintenance of behavioral arousal and reactivity but not in electrocortical awakening [19], might account to some extent for the slow progress on this subject. Lesion approaches can, however, produce collateral damage to adjacent brain structures, such as medial VTA glutamatergic neurons with afferents to the medial prefrontal cortex (mPFC) [20]. Such damage may in turn have effects on sleep behavior and the cortical EEG beyond those due to the lesioning of the dopaminergic midbrain neurons. Results from in vivo microdialysis experiments in combination with EEG recording indicate that extracellular dopamine levels in the mPFC and NAc are high during wakefulness and REM sleep, but significantly lower during NREM sleep [21]. The observation of high levels of dopamine during REM sleep in the NAc may indicate that dopamine can cause arousal independent of movement. By contrast, there is evidence that movement is inhibited during REM sleep by brainstem mechanisms that produce spinal atonia, and that animals with pontine lesions can show active behavior during REM sleep [22,23]. Thus, it is possible that NAc neurons are active during REM sleep, but their impact on movement is blunted by the actions of pontine atonia mechanisms. 725

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Critical role of the adenosinergic system in the BG for the sleep–wake cycle Adenosine promotes sleep by acting through the A1 receptor and A2A receptor, although the relative contribution of these receptors to sleep induction remains controversial [2,3]. The brain substrates through which adenosine acts on inhibitory A1 and excitatory A2A receptors to produce sleep are not well understood. It has been shown that adenosine acting via the A1 receptor induces sleep by inhibiting arousal-related cell groups surrounding the striatum, such as the horizontal limb of the diagonal band of Broca, the substantia inominata [32,33], and orexin neurons in the lateral hypothalamus (LHA) [34]. A previous study suggested that activation of A1 receptors in the tuberomammillary nucleus (TMN) also promotes NREM sleep by inhibiting the histaminergic system [35]. By contrast, stimulation of A1 receptors in the lateral preoptic area of the hypothalamus promotes wakefulness [36], supporting the idea that A1 receptor-mediated effects on sleep and wakefulness are region-specific ones. In fact, infusion of the A1 receptor agonist N6-cyclopentyladenosine (CPA) into the lateral ventricle of mice does not change the amounts of NREM and REM sleep [37], which may indicate opposing effects on sleep and wakefulness in different 726

areas of the brain. CPA can, however, produce dose-dependent increases in EEG slow-wave activity in NREM sleep when administered systemically or intracerebroventricularly in the rat [38]. The A1 receptor is expressed abundantly in the CPu and GP [39], and anatomical and pharmacological evidence suggests that activation of A1 receptors negatively affects the binding of dopamine at D1 receptors [40,41]. However, the roles played in the striatum by the functional interactions between A1 receptors and D1 receptors on striatonigral neurons for regulation of (a)

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In fact, deletion of the D2 receptor from the entire animal leads to a significant decrease in wakefulness with a concomitant increase in NREM and REM sleep, as well as drastically lower delta power in NREM sleep [24]. Such D2 receptor knockout mice frequently enter sleep after short periods of wakefulness during the nocturnal phase. Although these studies clearly show that the D2 receptor has a crucial role in maintaining wakefulness during the normal wake phase, it is impossible to identify the neural substrates involved in dopaminergic modulation of behavioral states. A previous study found a similar decrease in wakefulness after neurotoxic lesioning of the ventral periaqueductal gray (vPAG) dopaminergic neurons, but this effect was observed throughout the sleep–wake cycle [25]. Therefore, the effect observed only during the nocturnal phase in global D2 receptor knockout mice may not be exclusively regulated by the vPAG, but may also result from activation of D2 receptors in additional areas, perhaps the striatum. This assumption is supported by the fact that the D2 receptor agonist quinelorane directly applied to the NAc increases wakefulness in rats, whereas a D2 receptor antagonist induces sleep when injected into this same region [26]. Excessive sleepiness in PD and other sleep disorders, such as narcolepsy, shift-work sleep disorder, and obstructive sleep apnea–hyponea syndrome, are commonly treated with modafinil, a wake-promoting compound [27,28]. Modafinil enhances extracellular levels of dopamine in the NAc and mPFC [29]. The arousal effect of modafinil is abolished in mice with knockout of the dopamine transporter, through which dopamine is primarily cleared from the synapses [30]. A recent study that investigated the effects of administering D1 receptor antagonists to D2 receptor knockout mice found that the arousal effect of modafinil is exclusively mediated by both D1 and D2 receptors, with D2 receptors being of primary importance [31].

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Figure 2. The arousal effects of caffeine are abolished in rats with site-specific deletion of A2A receptors (A2AR) in the shell of the nucleus accumbens (NAc). To identify the neurons on which caffeine acts to produce arousal, A2A receptors were focally depleted by bilateral injections of adeno-associated virus carrying shorthairpin RNA for the A2A receptor into the (a) core or (b) shell of the NAc of rats [4]. Typical hypnograms that show the time course of changes in wakefulness and in rapid eye movement (REM) and non-REM (NREM) sleep after administration of caffeine at a dose of 15 mg/kg indicate that rats with shell, but not core, knockdown of the A2A receptor show a strongly attenuated caffeine arousal. Gray areas in the hypnograms represent wakefulness after caffeine administration that correspond to depletion of A2A receptors in the core or shell of the NAc. For caffeine to be effective as an A2A receptor antagonist, excitatory A2A receptors on NAc shell neurons must be tonically activated by adenosine, suggesting that A2A receptors on neurons in the NAc shell contribute to restraint of the arousal system whereby caffeine can override the ‘adenosine brake’, promoting arousal. Hypnograms adapted, with permission, from [4].

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the sleep–wake cycle remain to be elucidated. Antagonistic interactions between the inhibitory A1 receptor and excitatory D1 receptor may suggest that striatal A1 receptors negatively affect movement and behavioral arousal. By contrast, CGS21680, a highly selective A2A receptor agonist, leads to profound increases in NREM and REM sleep after infusion into the subarachnoid space underlying the ventral surface region of the rostral basal forebrain (BF) of rats or into the lateral ventricle of mice [37,42]. Interestingly, administration of CGS21680 to the rostral BF leads to expression of c-Fos predominantly within the shell of the NAc and the medial portion of the olfactory tubercle [43,44]. Direct perfusion of the A2A receptor agonist into the shell of the NAc induces NREM and REM sleep that corresponds to approximately three-quarters of the amount of sleep measured during subarachnoid space infusion of the A2A receptor agonist [43]. Interpretation of these results indicates that A2A receptors in or close to the NAc shell promote sleep.

Acting opposite to adenosine, caffeine enhances wakefulness. Caffeine binds to A1 and A2A receptors with very similar affinities and acts as an antagonist for both receptor subtypes [45]. Experiments using global genetic knockouts of A1 and A2A receptors reveal, however, that the A2A receptor, but not the A1 receptor, mediates the arousal effect of caffeine [5]. The specific role of A2A receptors in the BG was investigated using powerful tools for site-specific gene manipulations, such as conditional knockout of the A2A receptor in mice using Cre–Lox technology or local infection of rat brains with adeno-associated virus carrying short-hairpin RNA of A2A receptors to silence their expression [4]. Selective deletion of A2A receptors in the NAc shell resulted in abrogation of the effect of caffeine on wakefulness (Figure 2). Excitatory A2A receptors on neurons within the NAc shell must be tonically activated by adenosine for caffeine to be effective as an A2A receptor antagonist. This tonic activation can occur in the NAc shell because sufficient levels of adenosine are available under the most basal

Box 2. Neuronal mechanisms of sleep–wake regulation Monitoring of the EEG and electromyogram (EMG) has been instrumental in elucidating the mechanisms of sleep–wake regulation. In many sleep research laboratories, a cable-based sleep bioassay system is used to monitor the EEG and EMG in combination with software for automatic scoring of the vigilance states of freely moving rodents through power spectrum analysis of the fast Fourier transform (FFT) of the EEG (Figure I) [103]. Several interactions between sleep- and wake-active neurons have been proposed at the systems level in models of sleep–wake regulation. For instance, sleep is promoted by inhibition of cholinergic neurons in the basal forebrain, whereby slow-wave sleep is caused by inhibition of acetylcholine release by adenosine [104]. Another contemporary systems-level model of NREM sleep–wake regulation describes a flip–flop switching mechanism involving mutually inhibitory interactions between sleep-promoting neurons in the ventrolateral preoptic area (VLPO) and wake-promoting neurons in the brainstem and hypothalamus. The latter includes the histaminergic TMN, noradrenergic locus coeruleus (LC), serotonergic dorsal raphe nucleus (DR), and cholinergic pontine (pedunculopontine and laterodorsal tegmental, PPT and LDT) nuclei [7,8,57]. Aminergic neurons in the TMN, LC, and DR promote wakefulness via direct excitatory effects

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on arousal systems in the thalamus, hypothalamus, basal forebrain, and cerebral cortex, in addition to inhibition of sleep-promoting neurons in the VLPO. During sleep, the VLPO inhibits these arousalpromoting regions through GABAergic and galaninergic projections. The flip–flop model also predicts that orexin neurons of the LHA prevent unwanted transitions into sleep and thus stabilize wakefulness. However, even complete lesioning of the VLPO leads to a reduction in the amount of sleep by only approximately 50% over at least 3 weeks in rats [105], suggesting that other areas of the brain can also restrain the arousal system and promote sleep. A mutually inhibitory interaction between the ventral periaqueductal gray, lateral pontine tegmentum, and sublaterodorsal nucleus (SLD) in the brainstem has been proposed for switching in and out of REM sleep [106]. The REM sleep-inducing area in the SLD also contains two populations of glutamatergic neurons, one of which projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates muscle atonia during REM sleep. Modulation of REM versus NREM sleep is provided by cholinergic and monoaminergic systems in the PPT and LDT, LC, and DR, as well as by the VLPO and the orexinergic LHA.

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Figure I. Sleep bioassay system for rodents. (a) To monitor EEG signals, stainless steel screws are implanted epidurally over the frontal cortical area and the parietal area of one hemisphere. In addition, EMG activity is monitored via Teflon-coated wires bilaterally placed into both trapezius muscles. (b) In contrast to sleep stages, (i) wakefulness is characterized by low- to moderate-voltage EEG and the occurrence of EMG activity. (ii) NREM sleep can be identified by the appearance of large, slow brain waves with a delta rhythm below 4 Hz (orange frequencies in the FFT of the EEG). (iii) At the transition from NREM to REM sleep, there is a shift from lowfrequency delta activity to a rapid low-voltage EEG in the theta range between 6 and 10 Hz (blue frequencies in FFT of the EEG).

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conditions and A2A receptors are abundantly expressed throughout the striatum, including the NAc shell [46,47]. Thus, activation of A2A receptors on neurons in the NAc shell contributes to restraint of the arousal system, whereby caffeine can override the ‘adenosine brake’ to promote wakefulness. Interestingly, deletion of the dopamine transporter reduces NREM sleep, increases wakefulness, and unmasks hypersensitivity to the wake-promoting effects of caffeine [30]. The last observation may indicate that expression of accumbal D2 receptors working opposite to A2A receptors is involved in the arousal effect of modafinil. Despite the fact that stimulation of A2A receptors leads to a decrease in affinity for dopamine at D2 receptors via intramembrane interaction and to a reduction in Gi protein coupling of the D2 receptor for inhibition of cAMP production [48], adenosine and its antagonists, such as caffeine, can modulate the activity of MSNs in the striatum via A2A receptors independently of D2 receptors [49,50]. Integrating the NAc into the sleep–wake regulatory network A heuristic model that links the traditional BG pathways for locomotion and motivational behavior to the more classical circuitry for sleep (Box 2) would greatly enhance our knowledge of sleep–wake regulation. In particular, afferents of the NAc uniquely position the ventral striatum as a crucial site of convergence for emotional content from the amygdala, contextual information from the hippocampus, motivational significance through dopaminergic inputs, and executive or cognitive information from the prefrontal cortex. A2A receptors in the NAc that are critical for the arousal effect of caffeine probably modulate neural substrates through which dopamine may also produce arousal (Figure 3). The NAc has GABAergic projections

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to a wide range of targets, including the ventral pallidum (VP), the LHA, the parabrachial nucleus (PB), and the VTA, that may contribute to wakefulness, as described in greater detail below. Therefore, it can be hypothesized that NAc activation exerts inhibitory effects on important arousal systems and promotes sleep. The NAc can reach the mPFC via the VP and thalamus (Figure 3, pathway a), which is a key executive interface between cognition and emotion but is also uniquely sensitive to sleep and sleep need [51–53] and might promote sleep [54]. The mPFC can provide top-down modulation through its direct descending projections to sleep–wake regulatory systems in the hypothalamus, such as the TMN, the LHA, and nuclei in the brainstem, including the locus coeruleus (LC) [55–57]. In the case of stress-induced insomnia, for example, lesioning of the infralimbic cortex, a subdivision of the PFC, reduces c-Fos expression in the LC and TMN, and restores NREM (but not REM) sleep in rats [58]. In addition, the NAc directly innervates orexin-containing neurons in the perifornical LHA and vesicular glutamate transporter 2-expressing neurons in the posterior part of the LHA (Figure 3, pathway b) [20,59,60]. Orexin neurons of the brain are a key integration site of interoceptive and homeostatic signals to increase wakefulness and suppress REM sleep, and selective loss of orexin neurons results in narcolepsy [61]. Although orexin neurons produce strong c-Fos expression in response to systemic caffeine [62], it appears that these neurons are not required for the promotion of wakefulness by caffeine [63]. By contrast, glutamatergic neurons in the posterior hypothalamus with projections to the cerebral cortex and BF enhance wakefulness, although their precise role in sleep– wake regulation remains to be determined [7].

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Figure 3. Model in which the nucleus accumbens (NAc) is an integral part of the sleep–wake regulatory network. Subserving the inhibitory output of the NAc (magenta round-headed lines), the activity of neuronal populations in the ventral pallidum (VP), the lateral hypothalamus (LHA), the parabrachial nucleus (PB), and the ventral tegmental area (VTA) is probably a major source of cortical arousal. (a) The pathway through the VP and thalamus includes descending projections of the medial prefrontal cortex (mPFC) to arousal-promoting neurons in the tuberomammillary hypothalamic nucleus (TMN), the LHA, and the locus coeruleus (LC). (b) Orexinergic and glutamatergic neurons in the LHA send major projections to the basal forebrain (BF) and cerebral cortex, but are also reciprocally connected to the non- rapid eye movement sleep–wake flip–flop switch (shown in gray; Box 2), including the ventrolateral preoptic area (VLPO), the TMN, and the LC. (c) The PB is an important component of the ascending arousal system and is strongly connected to the BF and LHA. (d) Glutamatergic neurons in the VTA may also relay a waking stimulus from the ventral striatum to the cerebral cortex. The NAc model predicts that adenosine acting on excitatory A2A receptors (A2AR) and working opposite to the inhibitory dopamine–D2 receptor (D2R) system, modulates the activity of medium spiny projection neurons in the NAc, inhibiting arousal. The plus sign represents excitatory receptors; the minus sign represents inhibitory receptors. Arrows represent excitatory synapses; round-headed lines represent inhibitory synapses; bars with both symbols represent reciprocal excitatory (arrows) and inhibitory (round-headed) connections.

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Opinion Moreover, neurons of the NAc shell, but not the NAc core, send projections to the PB in the pons (Figure 3, pathway c) [64,65]. The PB has recently been characterized as a key component of the ascending arousal system and, in fact, lesions of the PB cause coma [66]. The PB is the largest source of brainstem input to the BF and also has substantial projections to LHA. In the midbrain, reciprocal connections between the NAc and VTA may promote behavioral arousal driven by motivation (Figure 3, pathway d) [6], but it should be noted that the NAc projects exclusively to the medial part of the VTA, which is also a known

Box 3. Outstanding questions  Whereas the primary cause of dysfunctional movement and cognition is well understood in disorders related to the BG (e.g. for PD and HD), explanations for sleep abnormalities in patients with movement disorders are largely based on speculation. The differential roles of A2A and D2 receptors in the striatum in sleepiness observed in movement disorders need to be clarified. Is there a spatial causality or independence of D2 receptor function in the dorsal striatum versus NAc for movement and wakefulness?  According to studies that used neurotoxic lesioning and genetic deletion of the A2A receptor and D2 receptor, control of wakefulness in the BG seems to be largely specific to the indirect pathway; however, the role of neurons of the direct pathway in the regulation of sleep and wakefulness is not well understood. Transgenic methods in mice and rats can be used to genetically dissect the antagonistic roles played in the striatum by interactions between inhibitory A1 receptors and excitatory D1 receptors on striatonigral neurons for regulation of the sleep–wake cycle and to reveal the specific function of the direct pathway in behavioral arousal. It is known that the direct pathway predominates over the indirect pathway in processing of a rewarding input to the striatum–NAc [107], but it is unclear how the sleep–wake cycle is affected in this situation.  It remains unknown where and in what cell compartment of the striatum adenosine is generated. Extracellular adenosine levels can increase through intracellular formation and export via equilibrative transporters [69]. By contrast, genetic elimination of astrocytic exocytosis prevents accumulation of sleep pressure [108]. Therefore, it may be possible that release of ATP or ADP in a neurotransmitter-like fashion from striatal astrocytes or cortical pyramidal neurons projecting to the striatum is the dominant source of extracellular adenosine in the striatum. What is the role of the recently identified nucleotide transporter involved in vesicular storage and exocytosis of ATP in the production of extracellular adenosine [109]?  CB1 cannabinoid receptors are highly expressed in the striatum. Global genetic deletion of CB1 receptors has been linked to decreased locomotor activity and a deficit in habit learning [110,111], both of which are associated with the BG. Indeed, knockout of striatal A2A receptors results in impairment of habit formation but increased goal-oriented behavior and increased working memory [112]. Furthermore, part of the A2A receptormediated psychomotor effect depends on the CB1 receptor [113]. These findings raise the interesting possibility of a functional link between CB1 and A2A receptors for the control of arousal.  Disruption of sleep is a well-known but poorly understood side effect of opioids, including morphine [114]. The striatum contains the endogenous opioid peptides dynorphin (direct pathway) and enkephalin (indirect pathway), and the corresponding k-, m- and d-opioid receptors [115]. What are the effects on sleep and wakefulness of differential modulation of D1 receptor-containing striatonigral versus D2 receptor-containing striatopallidal MSNs by endogenous opioid peptides, such as dynorphin and enkephalin, or natural and semi-synthetic opiates, including morphine?

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source of cortically projecting neurons that contain glutamate as their neurotransmitter [20,67]. Caffeine induces cFos expression only in non-dopaminergic neurons of the medial VTA [62], and thus it is possible that the VTA leads to electrocortical awakening through excitatory projections to the cerebral cortex. Concluding remarks Physiological and environmental events affect the transition from one behavioral state to another, and it is now widely accepted that sleep is regulated by homeostatic (i.e. sleep pressure), circadian (i.e. daily rhythms), and allostatic (i.e. food availability or stress) factors. In the first case, the homeostatic process is controlled by sleep propensity, which increases during the course of wakefulness and dissipates during sleep [68]. It is thought that endogenous somnogenic substances, such as adenosine, prostaglandin D2, and cytokines, comprise the molecular basis of this so-called sleep homeostat that interacts with the sleep regulatory network [69–71]. By contrast, the circadian process is controlled by an internal pacemaker and is independent of prior sleep and waking. In mammals, this pacemaker is the suprachiasmatic nucleus in the hypothalamus; it influences not only the timing of sleep and wakefulness but also a wide range of other behaviors and physiological functions [7,72]. Stressful situations, such as a lack of food, predator confrontation, mating pressure, and seasonal migration, require rapid adjustment of the wake– sleep state towards high arousal, for which specific networks in the mPFC, amygdala, hypothalamus, and brainstem have been identified [58,73]. The ventral striatum has a unique capability to integrate behavioral functions and emotional events and has plausible efferents that may contribute to the regulation of sleep and waking. In our opinion, this would be an ideal site for promotion of wakefulness by behavioral processes that require consciousness, but locomotor and arousal systems are inhibited during sleep. The body of current work also leads us to suggest that motivation may be considered as a fourth fundamental principle (in addition to homeostatic, circadian, and allostatic factors) by which sleep and waking are regulated. Although many questions remain (Box 3), perhaps the most pressing issue is to identify which of the output projections of the striatum and the NAc relay the waking stimulus from the BG to the sleep–wake regulatory network and lead to cortical awakening. In future studies, this task may be accomplished using some of the most recent molecular biological technologies for systems-level sleep research in freely behaving animals. These technical advances include a wide range of approaches, from conditional deletion of genes based on Cre–LoxP technology to RNA interference [4,74] to modulation of neuronal activity using genetically engineered optical switches (e.g. channel rhodopsin) [75,76] to in vivo reversible silencing (e.g. nonmammalian Cl channels) [77] and activation (e.g. stimulatory GPC receptors) [78,79] of neurons. Many sleep abnormalities involving dysfunction of the BG, such as in PD and Huntington’s disease, have been described [16,80], but in almost all instances their etiological bases are unclear. This is related to the fact that the neuronal mechanisms subserving the pathogenesis of these 729

Opinion diseases remain unresolved. The BG are a prime example for a sleep–disease connection that creates a vicious cycle. Initially, movement disorders, psychiatric problems, and/or substance abuse disturb sleep, and the resulting sleep abnormalities further exacerbate the original BG dysfunction. A new level of anatomical and molecular analysis of the BG circuitry that regulates sleep–wake behavior may shed new light on the underlying mechanisms as well as potential treatment strategies for sleep disturbances associated with BG disorders. Acknowledgments Our research was supported by Japan Society for the Promotion of Science Grant 24300129 (to M.L.) and 22300133 (to Y.U.), a grant from the Ministry of Education, Culture, Sports, Science, and Technology (to Y.U.), a grant from the Ministry of Health, Labor and Welfare (to Y.U.), Ono Pharmaceutical Co. (to Y.U.), Takeda Pharmaceutical Co. (to Y.U.), Osaka City (to M.L., Z-L.H., and Y.U.), Grants-in-Aid for Scientific Research from the National Natural Science Foundation of China (31171010 and 31121061 to Z-L.H.), National Basic Research Program of China Grants (2009CB5220004, 2011CB711000, and 2009ZX09303-006 to Z-L.H.), Shanghai Leading Academic Discipline Project (B119 to ZL.H.), National Institutes of Health Grants NS041083 (to J-F.C.), NS062727 (to J.L.), and NS 061841 (to J.L.), and the Cogan Family Foundation (to J-F.C.).

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