Roles of the orexin system in central motor control.

Neuroscience and Biobehavioral Reviews 49 (2015) 43–54

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Roles of the orexin system in central motor control Bo Hu 1 , Nian Yang 1 , Qi-Cheng Qiao, Zhi-An Hu ∗ , Jun Zhang ∗∗ Department of Physiology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, PR China

a r t i c l e

i n f o

Article history: Received 21 August 2014 Received in revised form 10 November 2014 Accepted 3 December 2014 Available online 12 December 2014 Keywords: Orexin system Central motor control Motor cortex Brain stem motor nuclei Spinal cord motor circuitry Basal ganglia Cerebellum Motor activity Sleep/wake behavior Emotion behavior Energy homeostasis behavior

a b s t r a c t The neuropeptides orexin-A and orexin-B are produced by one group of neurons located in the lateral hypothalamic/perifornical area. However, the orexins are widely released in entire brain including various central motor control structures. Especially, the loss of orexins has been demonstrated to associate with several motor deficits. Here, we first summarize the present knowledge that describes the anatomical and morphological connections between the orexin system and various central motor control structures. In the next section, the direct influence of orexins on related central motor control structures is reviewed at molecular, cellular, circuitry, and motor activity levels. After the summarization, the characteristic and functional relevance of the orexin system’s direct influence on central motor control function are demonstrated and discussed. We also propose a hypothesis as to how the orexin system orchestrates central motor control in a homeostatic regulation manner. Besides, the importance of the orexin system’s phasic modulation on related central motor control structures is highlighted in this regulation manner. Finally, a scheme combining the homeostatic regulation of orexin system on central motor control and its effects on other brain functions is presented to discuss the role of orexin system beyond the pure motor activity level, but at the complex behavioral level. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Distribution of orexinergic fibers and receptors in the motor control system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 2.1. Orexinergic fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 2.2. Orexinergic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.2.1. Motor cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.2.2. Brain stem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.2.3. Spinal cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.2.4. Basal ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.2.5. Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Effects of the orexin system on various central motor control structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.1. Spinal cord motor circuitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.2. Brain stem motor nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 3.3. Motor cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 3.4. Basal ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 3.5. Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Functional relevance of the orexin system in the central motor control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 4.1. Characteristics of the orexin system’s effects on the central motor control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 4.2. Functional basis for the orexin system’s regulation on the central motor control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 4.3. The significance of the regulation on central motor control by orexin system at the behavioral level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

∗ Corresponding author. Tel.: +86 23 68752245. ∗∗ Corresponding author. Tel.: +86 23 68752246. E-mail addresses: [email protected] (Z.-A. Hu), [email protected] (J. Zhang). 1 Co-first authors. http://dx.doi.org/10.1016/j.neubiorev.2014.12.005 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

44

5.

B. Hu et al. / Neuroscience and Biobehavioral Reviews 49 (2015) 43–54

Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In the central nervous system, the orexins (or hypocretins), which consist of the two neuropeptides orexin-A and orexin-B, are produced exclusively by a specific group of neurons whose cell bodies are located in the lateral hypothalamic/perifornical area (LH/PFA) (Gautvik et al., 1996; de Lecea et al., 1998; Sakurai et al., 1998; Kukkonen et al., 2002). However, the orexins are released in nearly every brain area via their diffusely distributed axon terminals (Peyron et al., 1998; Cutler et al., 1999; Nambu et al., 1999; Kukkonen et al., 2002). Therefore, it is widely accepted that the LH/PFA orexin system is associated with multifaceted brain functions including the regulation of sleep and wakefulness cycle, feeding, reward processing, energy homeostasis, learning and memory, and so on (for reviews, see: Sutcliffe and de Lecea, 2002; Kukkonen et al., 2002; Siegel, 2004a; Harris and Aston-Jones, 2006; Kotz, 2006; Sakurai, 2007; Matsuki and Sakurai, 2008; Ohno and Sakurai, 2008; Adamantidis and de Lecea, 2009; Cason et al., 2010; Teske et al., 2010; de Lecea, 2012; Mahler et al., 2012; Mieda and Sakurai, 2012; Kukkonen, 2013; Chen et al., 2014; Li et al., 2014). Central motor control may be also the case. Central motor control is a basic function of the brain for regulating the movement activities with accurate strength, timing, direction, speed and location, and it involves many areas of the brain (Friston, 2011). Based on the anatomical connections, it has been generally assumed that central motor control system is made up of several isolable subsystems in the central nervous system, each with different capacities; the motor cortex, basal ganglia, brain stem, spinal cord, and cerebellum (Friston, 2011). These distributed subsystems function as a whole to control the optimal movements, which are essential for coordinating the voluntary movements of animals and humans. Intriguingly, all the subsystems implicated in central motor control have been demonstrated to be innervated by the fibers containing the orexins (see Table 1). In addition, the orexinergic receptors are widely

51 51 51

distributed in various central motor control subsystems but regionally selective (see Table 2). These findings thus raise the possibility that central motor control is under the direct modulation of the orexin system. Particularly, after the orexin deficiency, the affected motor activities have indeed been observed, such as the abnormal eyelid movement (Chee, 1968) and cataplexy (Chemelli et al., 1999). Besides, the rapid eye movement sleep (REM) behavior disorder in narcolepsy with cataplexy (RBDnc) is recently found to associated with orexin deficiency (Dauvilliers et al., 2013), although the relationship between the idiopathic REM behavior disorder (iRBD) and orexin system is still not clear (Anderson et al., 2010). However, how the various central motor control subsystems and related motor activity are directly influenced by the orexin system remains still enigmatic and attractive. Consequently, in this review, we will focus on the present literatures that describe the direct modulation of orexins on various motor control structures at the molecular, cellular, circuitry, and motor activity levels. This combination of researches at different levels will provide new insights into the functional relevance of orexins in the context of motor activity that is determined by the central motor control system. 2. Distribution of orexinergic fibers and receptors in the motor control system 2.1. Orexinergic fibers The cell bodies of the orexinergic neurons are strictly localized in the LH/PFA, but their fibers are widespread in the entire brain. Notably, nearly all the central motor control structures are innervated by the orexin-immunoreactive fibers, whereas the relative abundance of fibers in various central motor control regions may be distinctive (Table 1). The orexin-immunoreactive fibers with varicosities are widely distributed in cerebral cortical areas including the motor cortex (Peyron et al., 1998; Cutler et al., 1999; Date et al.,

Table 1 Relative density of orexin-immunoreactive fibers in the motor control system. Structure

Density

References

Motor cortex Layers I–II Layers III–IV Layers V–VI

Moderate Moderate Dense

Peyron et al. (1998) and Nambu et al. (1999) Peyron et al. (1998) and Nambu et al. (1999) Peyron et al. (1998) and Nambu et al. (1999)

Brain stem Oculomotor nuclei Hypoglossal motor nucleus Trigeminal motor nucleus Mesencephalic trigeminal nucleus Lateral vestibular nucleus

Sparse Sparse Sparse Moderate Moderate

Nambu et al. (1999) and Peyron et al. (1998) Peyron et al. (1998), Nambu et al. (1999) and Cutler et al. (1999) Peyron et al. (1998) and Cutler et al. (1999) Nambu et al. (1999) Peyron et al. (1998), Nambu et al. (1999) and Cutler et al. (1999)

Sparse

van del Pol (1999) and Date et al. (2000)

Dense Dense Sparse Dense Absent

Peyron et al. (1998) Peyron et al. (1998), Nambu et al. (1999) Nambu et al. (1999), Peyron et al. (1998) and Cutler et al. (1999) Peyron et al. (1998) and Nambu et al. (1999) Peyron et al. (1998)

Sparse Sparse Moderate

Cutler et al. (1999) and Nambu et al. (1999) and Peyron et al. (1998) Cutler et al. (1999), Nambu et al. (1999) and Peyron et al. (1998) Nambu et al. (1999)

Spinal cord Ventral horn Basal ganglia Striatum Subthalamic nucleus Globus pallidus Substantia nigra pars compacta Substantia nigra pars reticular Cerebellum Cortex Deep nuclei Flocculus


45

Table 2 Relative density of orexin-immunoreactive receptors in the motor control system. Structure

Orexin-1 receptor

Orexin-2 receptor

References

Motor cortex Layer III–IV Layer V–VI

Moderate Sparse

Sparse Moderate

Cluderay et al. (2002) and Trivedi et al. (1998) Hervieu et al. (2001) and Marcus et al. (2001)

Absent Sparse Sparse

Moderate Absent Sparse

Marcus et al. (2001) Marcus et al. (2001) Marcus et al. (2001) and Zhang et al. (2011)

Moderate

Sparse

Hervieu et al. (2001) and Marcus et al. (2001)

Basal ganglia Striatum Subthalamic nucleus Globus pallidus Substantia nigra pars compacta Substantia nigra pars reticular

Sparse Moderate Moderate Moderate

Moderate Sparse – –

Trivedi et al. (1998) Trivedi et al. (1998) and Marcus et al. (2001) Hervieu et al. (2001) and Marcus et al. (2001)

Cerebellum Cortex Deep nuclei

Sparse Moderate

Sparse Sparse

Hervieu et al. (2001) and Chen et al. (2013) Hervieu et al. (2001) and Chen et al. (2013)

Brain stem Hypoglossal motor nucleus Trigeminal motor nucleus Lateral vestibular nucleus Spinal cord (lumbar segment) Ventral horn

1999; Nambu et al., 1999; Taheri et al., 1999). Within the cortex, the highest distribution levels of the orexinergic fibers are found in the Layer VI (Peyron et al., 1998; Nambu et al., 1999). In addition, the orexinergic fibers are shown to innervate several motor nuclei in the brain stem (Fung et al., 2001; Zhang and Luo, 2002; McGregor et al., 2005; Mascaro et al., 2009; Schreyer et al., 2009). In the spinal cord, long descending axons that contain the orexinimmunoreactivity are revealed to be located in the ventral horn (van del Pol, 1999; Date et al., 2000). The relatively abundant orexinergic fibers are also detected in the basal ganglia, including the striatum, subthalamic nucleus, global pallidum, as well as the substantia nigra pars compacta and pars reticulate (Peyron et al., 1998; Cutler et al., 1999; Namnu et al., 1999; Korotkova et al., 2002; Baldo et al., 2003). At last, many parts of the cerebellum contain few orexin-immunoreactive fibers, but the flocculus, a relatively large number of orexinergic fibers are observed with a radical orientation (Nambu et al., 1999; Nisimaru et al., 2013). 2.2. Orexinergic receptors In addition to the orexinergic fibers, the orexinergic receptors have been demonstrated to be widespread in the central motor control subsystems, however, with diverse expression patterns in these various structures (Trivedi et al., 1998). To date, two orexinergic receptors have been identified, the orexin-1 and orexin-2 receptors, which belong to the G-protein coupled receptor superfamily with the preserved seven transmembrane domains (Sakurai et al., 1998). The relative abundance of orexin-1 and orexin-2 receptors in various motor control structures is summarized in Table 2. 2.2.1. Motor cortex Overall, both the orexin-1 and orexin-2 receptors have been found to be diffused throughout all layers of the primary motor cortex (see Table 2). Interestingly, the orexin-1 receptor immunostaining is particularly detected in the layers III and IV (Hervieu et al., 2001), whereas the orexin-2 receptor immunoreactivity is detected in the layers V and VI (Cluderay et al., 2002). In addition, cell-staining in the motor cortex is predominately labeled on the surface membrane (Hervieu et al., 2001; Cluderay et al., 2002). 2.2.2. Brain stem Low (or moderate) levels of orexin-1 and orexin-2 receptors have been revealed to be distributed in the brain stem motor nuclei such as the lateral vestibular nucleus (LVN), hypoglossal nucleus,

and trigeminal motor nucleus (see Table 2; Marcus et al., 2001; Zhang et al., 2011). 2.2.3. Spinal cord To date, the examination of the orexinergic receptor distribution in the spinal cord has mainly focused on the lumbar segments. There is strong orexin-1 receptor mRNA and protein immunolabeling in the lumbar part of the spinal cord (see Table 2; Hervieu et al., 2001). In these segments, all subdivisions of the spinal gray matter including the dorsal and ventral horns are immunolabeled. By contrast, Laminae 2 and 10 are strongly or moderately labeled with the orexin-2 receptor immunoreactivity while a diffuse staining is obtained elsewhere (Cluderay et al., 2002). 2.2.4. Basal ganglia Orexinergic receptor-staining in the basal ganglia is particularly observed in the substantia nigra compacta, medial globus pallidus, and caudate-putamen with moderate density (see Table 2; Hervieu et al., 2001; Cluderay et al., 2002). Besides, the abundance of the orexin-1 receptor is comparable to that of the orexin-2 receptor all around the basal ganglia. 2.2.5. Cerebellum The density of orexinergic receptors is relatively sparse in the cerebellum (see Table 2). Recently, the orexin-1 receptor-like protein has been specifically observed in Purkinje cells in the cerebellar cortex (Chen et al., 2013). In contrast, the orexin-2 receptor immunolabeling is dense or moderate in the molecular and granular layer of the cerebellar cortex (Nisimaru et al., 2013). In the deep cerebellar nuclei (DCN), both the orexin-1 and orexin-2 receptors have been identified (Hervieu et al., 2001; Cluderay et al., 2002). Taken together, the broad distribution of orexinergic fibers and receptors in various central motor control structures strongly raise a possibility that the orexin system is directly involved in central motor control. 3. Effects of the orexin system on various central motor control structures 3.1. Spinal cord motor circuitry We begin by discussing the influence of orexin system on the spinal cord motor circuitry. The spinal cord is the station where the transmission between the central nervous system and the rest of the body happens. The ventral horn of the spinal cord, which

46


contains the spinal cord motor circuitry, functions primarily in the transmission of motor command from the central motor control system to the muscles of the body. Intriguingly, long descending axons containing orexins have been reported to reach the spinal cord of rats (Cutler et al., 1999; Taheri et al., 1999). Detailed investigations have further revealed that the orexinergic fibers innervate all levels of the rat spinal cord, from the cervical to the sacral segments, and exhibit extensive divergence as demonstrated by a wide distribution in transverse sections (van den Pol, 1999; Date et al., 2000). Specifically, orexinergic fibers have been revealed to innervate the ventral horn of the spinal gray matter, which is the final common pathway for somatic movement. Additionally, strong orexin-1 and orexin-2 receptor immunoreactivities exist in the dorsal and ventral horns of the rat spinal cord (Hervieu et al., 2001; Cluderay et al., 2002). The presence of orexinergic fibers and receptors in the ventral horn hence suggests that the function of the spinal cord motor area may be directly influenced by the orexin system. In support of the suggestion mentioned above, the activities of lumbar motoneurons are strongly influenced via the direct orexinergic projections. In an elegant study, Yamuy et al. (2004) reported that the electrical microstimulation of the PFA results in the membrane depolarization and hence promotes the discharge of cat lumbar motoneurons. Further, it has been verified that the excitatory effects of the hypothalamic stimulation are mediated via the activations of orexin-1 receptors in the lumbar motoneurons (Yamuy et al., 2004). These findings suggest that the orexinergic neurons have the capacity to directly regulate the excitability and activity of motoneurons in the ventral horn. Interestingly, the orexin system might modulate the lumbar motoneurons in a statedependent manner. Juxtacellular application of orexins induces the excitation of lumbar motoneurons under general anesthesia control condition, whereas the inhibition of motoneurons is enhanced during carbachol-induced REM sleep-like atonia (Yamuy et al., 2010). Although the distribution of orexinergic fibers and orexinergic receptors in the ventral horn of the spinal cord and their influence on motoneurons are understood, the functional significance at motor activity level remains largely unclear. The limited findings that are available on this subject come from studies of the influence of the orexin system on breathing movement. The orexin-1 receptors are located in the cervical (C3–C4) motoneurons that innervate the diaphragm muscles (Young et al., 2005; Badami et al., 2010). Moreover, the activations of orexin-1 receptors via the perfusion of orexin-A increase the diaphragm electromyographic activities. The finding indicates that the orexin system may directly be involved in regulating the breathing. Together with previous discussed results form Yamuy et al. (2010), it further suggests that orexin system may potentially play a role in the pathophysiology of sleep-related respiratory disorders (Tarasiuk et al., 2014; Moore et al., 2014). 3.2. Brain stem motor nuclei The orexinergic fibers reach all levels of the brain stem including the midbrain, pons and medulla, in which a series of motor nuclei are believed to participate in the central motor control. These motor nuclei play distinct roles in central motor control but can be roughly divided into two subgroups according to the targets that they innervate. One group of the motor nuclei comprises the motoneurons that directly innervate the muscles in the head and face. The other group innervates the motoneurons in the brain stem and spinal cord. In the first group of brain stem motor nuclei, the functional connections of the visuomotor nuclei, hypoglossal motor nucleus, and trigeminal motor nucleus with the orexin system have been investigated. Special attentions have been paid to these three areas

mainly because the muscle fibers that they innervate, including the oculomotor, tongue, and masticatory muscles. They all are critically involved in several clinical symptoms induced by the orexin deficiency. These symptoms include the abnormal eyelid movement (Chee, 1968), respiration (Williams and Burdakov, 2008), and feeding (Siegel, 2004b). It is well-known that the visuomotor nuclei contain various functional motoneuron subgroups that contribute to oculomotor movements in several different ways (Büttner-Ennever et al., 2001; Büttner-Ennever, 2006). Within these nuclei, however, detailed morphological observations have further shown that only the motoneurons supplying the multiply innervated extraocular muscle fibers and the motoneurons innervating the levator palpebrae muscle fibers receive the strong orexinergic inputs (Schreyer et al., 2009). These findings hence suggest that the orexin system may be specifically involved in modulating oculomotor movements such as the eye alignment, convergence and eyelid position. It is said that the differential orexinergic innervation of the visuomotor nuclei correlates with the differential modulation of these motor nuclei and related oculomotor movements by the orexin system (Schreyer et al., 2009). By contrast, in the hypoglossal and trigeminal motor nuclei, the orexinergic fiber varicosities appear to locate nearby the soma and dendrites of motoneurons in the different subgroups. They innervate functionally distinctive (synergistic and antagonistic) muscle groups (Fung et al., 2001), indicating another modulation pattern, in which the orexin system exerts the global influence on multiple groups of the motoneurons in these two nuclei. In the same report, retrograde tracing and double labeling results showed that the direct projections from the hypothalamus to hypoglossal motoneurons indeed contain orexinergic afferents (Fung et al., 2001). In line with these results, the activations of LH, which contain the orexinergic neurons, elicit obvious motoneuronal activations in the hypoglossal motor nucleus independent of the premotor aminergic activations in the brain stem (Fenik et al., 2009), which might indirectly affect the hypoglossal motor nucleus. The morphological and electrophysiological results mentioned above indicate that the orexin system may exert direct and global effects on the hypoglossal motor nucleus. Given the observations that the application of orexins to the hypoglossal motor nucleus increases the activity of the genioglossus muscle (Peever et al., 2003), these effects have been proposed to be functionally important. Furthermore, the same authors reported a similar promotion of the activity in the masseter muscle after the application of orexins into the trigeminal motor nucleus, revealing the functional significance of the direct global effect of orexin system on the trigeminal motor nucleus (Peever et al., 2003). But in this study, the underlying mechanisms are reported to involve the presynaptic glutamate release and NMDA receptors (Peever et al., 2003). Although several studies have provided further confirmation that the orexinergic fibers can directly innervate the trigeminal motoneurons (Zhang and Luo, 2002; McGregor et al., 2005; Mascaro et al., 2009) and that the orexinergic receptors are present in the neurons of trigeminal motor nucleus (Greco and Shiromani, 2001), the relationship between the orexin system and the glutamatergic processes in the trigeminal motor nucleus is still unknown. In the second group of brain stem motor nuclei, the gigantocellular reticular nucleus (Gi), lateral vestibular nucleus (LVN), and mesencephalic trigeminal nucleus (MTN) have thus far been investigated. Mileykovskiy et al. (2002) found that the injection of orexins into the Gi produces bilateral hindlimb muscle atonia in decerebrate rats. The effect of orexins on the Gi is similar to that of electrical stimulation on the Gi, implying that the orexin system may directly regulate the activity of Gi neurons participating in muscle tone suppression (Mileykovskiy et al., 2002).


In a series of experiments made by Zhang et al. (2011), the direct postsynaptic excitatory effects of the orexins on the LVN neurons are revealed, and the underlying mechanisms are clarified to involve both the activation of Na+ –Ca2+ exchangers and the closure of inwardly rectifying K+ channels. More interestingly, the activation of Na+ –Ca2+ exchangers and closure of inwardly rectifying K+ channels by orexins might influence the activity and the sensitivity of the LVN neurons, respectively, and correlate with the increases in the output and responsiveness of the entire nucleus to the external stimuli. These notions are evidenced by the obvious improvements in both the balance beam performance and negative geotaxis performance after the microinjection of orexins into the LVN. Furthermore, although the benefits to the balance and posture are clear, the effects of endogenous orexins on the LVN-mediated balance and posture are exhibited under specific circumstances, i.e., when an animal faces a major motor challenge. These findings thus reveal a novel effect pattern of the orexin system on the LVN and a corresponding functional significance for these effects at the motor activity level (Gao and Horvath, 2011). Additionally, at the level of the midbrain, neuronal activity may also be modulated by the effects of orexins on the MTN (which innervates the trigeminal motor nucleus), as morphological studies have demonstrated that both the orexinergic fibers (Zhang and Luo, 2002; Stoyanova and Lazarov, 2005; Mascaro et al., 2009) and orexinergic receptors are present in the MTN (Greco and Shiromani, 2001). Morphological studies have further shown that the density of orexinergic fibers and terminals in the MTN increases dramatically along the caudal-to-rostral axis (Stoyanova and Lazarov, 2005), which suggests a somatotropic arrangement of the orexinergic projections in the MTN. Thereby, in contrast to the visuomotor nuclei and the LVN, a different pattern of the orexinergic innervation substantially exists in the MTN, but the corresponding functional significance requires further investigation. On the basis of the preceding findings, we propose that the orexin system may exert diverse roles in the brain stem motor nuclei. In particular, the roles are highlighted by the distinct patterns of orexinergic projections, orexinergic receptors, and orexin effects that we have discussed above, suggesting that the orexin system may have differentially functional significance in brain stem motor nuclei and related motor control functions. 3.3. Motor cortex The motor cortex is tightly related to the programming and generation of voluntary movements, and consequently plays critical roles in the central motor control. It has been demonstrated that the ascending orexinergic fibers reach the motor cortex (Date et al., 1999). In general, the orexin system may influence cortical neuronal activity in two ways. First, the orexins cause presynaptic excitation in the terminals of the nonspecific thalamo-cortical projection system and then influence the activity of cortical neurons in all layers (Lambe and Aghajanian, 2003). Second, through a direct postsynaptic excitatory effect, the orexins exclusively excite the cortical neurons in the layer VI-b (Bayer et al., 2004). Currently, the latter mechanism has been demonstrated to occur in the motor cortex and the underlying receptor and ionic mechanisms are the activations of orexin-2 receptors and the blockage of potassium conductance, respectively (Bayer et al., 2004). In other words, it is likely that not all of the layers in the motor cortex are directly modulated by the orexin system. Despite this limited direct modulation, however, the ultimate influence of the orexin system on the motor cortex may be widespread. This possibility is raised because the neurons in the layer VI-b send corticocortical projections to the layer I and the neurons in layer I project strongly to all the deep cortical layers (Clancy and Cauller, 1999; Reep, 2000). Thus, the direct

47

modulation of the layer VI-b neurons by the orexin system may subsequently spread to the entire motor cortex. What is the functional significance of the orexinergic modulation on the motor cortex? To date, it is reasonable to speculate that the orexin system functions as promoting the voluntary movements, since the orexins diffusely excite the neurons in the motor cortex. In line with this speculation, the resting and active motor thresholds of the motor cortex (determined by the intensity of transcranial magnetic stimulation) are significantly higher in human narcoleptic patients than in normal controls, due to the loss of orexins (Oliviero et al., 2005). Additionally, in the traumatic brain injury patients who exhibit the sleep-wake and the extracellular orexin disturbances (Willie et al., 2012), the resting motor thresholds are higher than those of the normal controls (Nardone et al., 2011). These phenomena thus reflect hypoexcitability in the motor cortex after the loss of orexins (Nardone et al., 2011; Willie et al., 2012). In a situation more common than the stimulation-evoked motor activity discussed above, the orexin knockout mice exhibit a slight but significant decrease in voluntary motor activity compared with the wild type animals (Hara et al., 2001; Mieda et al., 2004; Mochizuki et al., 2004). However, the orexin knockout mice exhibit ˜ et al., normal voluntary movement initiation and speed (Espana 2007). Therefore, the decreased excitability of the motor cortex induced by the loss of orexins may not influence the ability to produce the voluntary movements but instead influence the probability of the occurrence of voluntary movements. This notion is consistent with the findings from previously discussed studies (Oliviero et al., 2005; Nardone et al., 2011), i.e., the elevated motor thresholds are caused by pronounced intracortical inhibition of the functional circuitry instead of the dysfunction in the motor cortex. 3.4. Basal ganglia Anatomically, the basal ganglia is composed of neurons from a group of functionally related subcortical nuclei, including the striatum, subthalamic nucleus, global pallidum, as well as the substantia nigra pars compacta and pars reticulate. It is important for planning, organizing and coordinating the movements and posture. Although all important subregions of the basal ganglia have been found to be innervated by orexinergic fibers and equipped with orexinergic receptors (see Table 1), detailed observations of the direct effect of orexins on the basal ganglia are limited. In the available literatures on this issue, there are controversial reports that the orexins selectively excite GABAergic neurons instead of dopaminergic neurons in the substantia nigra in vitro (Korotkova et al., 2002), but the haloperidol- or olanzapine-induced activations of orexinergic neurons increase the firing of dopaminergic neurons in the substantia nigra pars compacta via the activations of the orexin-1 receptors in vivo (Rasmussen et al., 2007). However, the latter result may require further investigation to make sure the involvement of direct activations of the orexin-1 receptors in the substantia nigra dopaminergic neurons, since the SB-334867, a selective orexin-1 receptor antagonist, is injected intravenously (Rasmussen et al., 2007). In this case, the orexin-1 receptors across the entire brain might be diffusely influenced. Another important report concluded that the orexins potentiate AMPAR-mediated synaptic transmission in the striatum (Shin et al., 2009), possibly by regulating the neuronal surface expression of AMPAR. This finding, although limited, together with the broad distribution of the orexinergic innervation and receptors in the basal ganglia allows us to propose that the orexins can directly modulate the activity of sub-nuclei of the basal ganglia. Unfortunately, researches of the functional influence of the orexin system on motor outputs mediated by the basal ganglia as a whole remain to be lacking. Nevertheless, the functions of orexins in the basal ganglia might be similar to that in the motor cortex,

48


as the microinjection of orexins into the substantia nigra pars compacta apparently elevates the time that the rats spend moving (Kotz et al., 2006). 3.5. Cerebellum It is generally accepted that the cerebellum, a classical subcortical structure, plays an important role in central motor control (D’Angelo et al., 2011). Initially, a study utilizing the immunochemical techniques revealed no orexinergic projections from the LH to the cerebellum in rats (Peyron et al., 1998). Subsequently, evidence supporting the existence of orexinergic terminals in the cerebellum has accumulated (Cutler et al., 1999; Nambu et al., 1999; Nisimaru et al., 2013). Indeed, the presence of orexin-immunoreactive fibers in the cerebellum has been reported, and the fibers range from a highly specific localized region, the flocculus, to broad areas in both the cerebellar cortex and the DCN in rats. In addition to the orexinergic fibers, both the orexin-1 and orexin-2 receptors have been detected in the rat cerebellum (Hervieu et al., 2001; Cluderay et al., 2002), although the earlier studies showed negative results based on in situ hybridization techniques (Trivedi et al., 1998; Marcus et al., 2001). Most recently, Chen et al. (2013) found that the orexin-1 receptors are specifically localized on the soma of Purkinje cells and large DCN neurons (>15 ␮m in soma diameter) in the cerebellum of guinea pigs. Taken together, the distributions of the orexin-containing fibers and orexinergic receptors imply that the function of the cerebellum may be under the direct influence of the orexin system (Ito, 2009; Manto and Oulad Ben Taib, 2010; Zhang et al., 2013). Indeed, the direct influence of orexinergic projections on the neuronal activity of the cerebellum has been demonstrated. It has been reported that the orexin-immunopositive axons have excitatory effects on Purkinje cells in the flocculus of rats (Nisimaru et al., 2013). Likewise, the excitatory effects of orexins on DCN neurons have been observed. Yu et al. (2010) reported that the application of orexins induces concentration-dependent excitatory neuronal activity responses in the rat DCN via the activations of orexin-2 receptors. Considering that the Purkinje cells and the DCN neurons are the final outputs of the cerebellar cortex and the DCN, respectively, it is feasible to propose that the orexinergic afferents from the LH/PFA may endogenously tune the neuronal outputs of the cerebellum and hence actively participate in central motor control (Ito, 2009; Manto and Oulad Ben Taib, 2010; Zhang et al., 2013). To date, two lines of evidence have implicated the involvement of the orexin system in the cerebellum-dependent motor control. One is that the impairment in the function of the orexin system causes hypotonia, a deficit that is classically observed after acute cerebellar lesions (Takakusaki et al., 2005). The other one is that a mouse model for phenylketonuria is accompanied by the prominent signs of hyperactivity and high levels of orexins in the cerebellum (Surendran et al., 2003). However, further investigations are guaranteed to directly determine the physiological significance of orexin system in cerebellum-dependent central motor control. Additionally, the cerebellum may influence central motor control via its essential role in motor learning (Medina and Mauk, 2000; De Zeeuw and Yeo, 2005). Recently, evidence for the direct participation of orexin system in the cerebellum-dependent motor leaning is uncovered. Chen et al. (2013) reported that interfering with endogenous orexins in the cerebellum via SB-334867 disrupts the adaptive timing of trace-conditioned eyeblink responses in guinea pigs. The underlying mechanism is revealed at the neuronal assembly level. Interfering with the endogenous orexin transmission in the cerebellum via SB-334867 prevents the increase in the amplitude of cerebellar theta-band (4.0–10.0 Hz) oscillation of the local filed potential (Chen et al., 2013), which normally accompanies

with motor learning (Hoffmann and Berry, 2009; Wikgren et al., 2010). Together with the findings that theta-frequency resonance at the cerebellar input stage improves spike timing and plasticity induction in the cerebellum (D’Angelo et al., 2001; Gandolfi et al., 2013); these observations provide a new perspective on the participation of the orexin system in the regulation of cerebellumdependent motor learning and then the motor control function.

4. Functional relevance of the orexin system in the central motor control 4.1. Characteristics of the orexin system’s effects on the central motor control As is revealed in the preceding summarization, the orexin system actively participates in the central motor control through the direct modulation effects on various motor control subsystems. Interestingly, the ascending and descending orexinergic projections may exhibit diverse modulation effects on motor control subsystems that they respectively innervate and, consequently, on the related functional aspects of the motor control. As shown in Fig. 1, the ascending orexinergic fibers reach the motor cortex and basal ganglia, which are two structures that are critically involved in voluntary movements. Although the innervation patterns of orexinergic fibers are distinct in these two areas (i.e., the orexinergic fibers specifically innervate layer VI neurons in the motor cortex but diffusely innervate neurons in all important sub-nuclei of the basal ganglia), the consequence of the differential innervation patterns is similar (see Sections 3.3 and 3.4). As such, the orexinergic innervation influences the entirety of both structures through the excitatory modulation on all architectural types of neurons. Importantly, this broad excitation may be ultimately translated into a functionally significant role for the orexin system in the promotion of voluntary movements. Consistent with this notion, the orexin deficiency in the motor cortex cause increases in the resting and active motor thresholds (Oliviero et al., 2005; Nardone et al., 2011). Likewise, the microinjection of orexins into the substantia nigra pars compacta significantly elevates the time spent for moving (Kotz et al., 2006). Additionally, at the circuit level, it has been proposed that the increase in the motor thresholds observed in the orexin deficiency results from the pronounced intracortical inhibition of functional circuitry in the motor cortex. Notably, this mechanism seems not to have phasic characteristics (Nardone et al., 2011; Willie et al., 2012). This finding thus indicates that the hypoexcitability of the motor cortex persists after the orexin deficiency, regardless of the circumstances, and that modulation of the orexin system on the motor cortex is tonic, but not phasic. The descending orexinergic fibers innervate the brain stem motor nuclei, spinal cord motor area, and cerebellum, but the patterns of the innervation are more diverse. These fibers are globally distributed in certain motor structures (such as the hypoglossal motor nucleus, the trigeminal motor nucleus, the LVN, and the spinal cord motor area), but are asymmetrically arranged in simple architectural motor structures (i.e., MTN), or selectively innervate complex architectural motor structures (i.e., visuomotor nuclei and cerebellum). Furthermore, as discussed in Sections 3.1, 3.2 and 3.5, the patterns of modulation effects of the descending orexinergic fibers on the innervated motor structures are also diverse. Interestingly, of the diverse orexin effects, those with phasic characteristics have been investigated most carefully. For example,


49

Fig. 1. Most prominent characteristics of the orexin system’s effects on motor control structures and their corresponding influences on motor activities from the present knowledge. The orexin system innervates the motor cortex and basal ganglia through the ascending fibers, whereas it innervates the cerebellum, brain stem motor nuclei, and spinal motor area through the descending fibers. In general, the key difference is that the orexin system may tonically excite the motor cortex and basal ganglia, but may modulate the cerebellum, brain stem motor nuclei, and spinal motor circuitry in a phasic manner, although the underlying molecular, cellular, and circuitry mechanisms are diverse and complex and need further investigations as indicated in text. Most importantly, through these modulations, orexin system can actively participate in the central motor control and then differentially influence related motor activities. Indeed from the present knowledge, the broad excitation on the motor cortex and basal ganglia by orexin system increases voluntary movements in a sustained way (inset A; referred to: Oliviero et al., 2005; Kotz et al., 2006; Nardone et al., 2011). Otherwise, the modulation of orexin system on the lateral vestibular nucleus (LVN) of brain stem is functionally significant for promoting the balance and postural motor activities, only when facing a major motor challenge (inset C; referred to: Zhang et al., 2011). Moreover, according to under the wakefulness or REM states, the modulation of orexin system on spinal cord motor neurons has excitatory or inhibitory influences on the muscle tone activity respectively (inset D; referred to: Yamuy et al., 2010). However, the functional significance of the possibly phasic modulation on cerebellum by orexin system is still lack of investigation (inset B).

the modulation effects of the orexin system are functionally significant in the LVN neurons only under specific circumstances or states (see Section 3.2, Zhang et al., 2011), and the opposite effects appear in the spinal cord motor neurons under different states (see Section 3.1, Yamuy et al., 2010). These observations hence suggest that substantial differences may exist between the modulation effects of the ascending and those of the descending orexin innervation on their respective motor structures, and at least one of the key to these differences may be related to phasic activity (Siegel, 2004b) (Fig. 1). 4.2. Functional basis for the orexin system’s regulation on the central motor control One possible explanation for the differential modulation on various motor control structures between the ascending and the descending orexinergic innervation is due to the involvement of different subgroups of orexinergic neurons (see Fig. 2). This possibility is raised by the evidence that the orexinergic neurons in the LH/PFA exhibit heterogeneity in the gene expression profiles (Dalal et al., 2013), the expression of vesicular glutamate transporters (Rosin et al., 2003), the responses to extracellular glucose concentration (Williams et al., 2008), the display of voltagegated currents and synaptic inputs (Schöne et al., 2011), and the vulnerabilities to Huntington’s disease (Williams et al., 2011), adverse environmental conditions (Pinos et al., 2011), stimulatory effect of ethanol (Morganstern et al., 2010), or intra-accumbens shell muscimol treatment (Baldo et al., 2004). Moreover, LH and PFA orexinergic neurons have been implicated in distinct brain functions including the reward processing/addiction (Aston-Jones

et al., 2009, 2010; Richardson and Aston-Jones, 2012) and the coordinated panic responses (Johnson et al., 2012), respectively. Even more, the orexinergic innervation to the different subdivisions of dorsal raphe has been found to originate from different orexinergic neurons (Lee et al., 2005). Obviously, the different origins of orexinergic neurons, and the subsequent different patterns of the orexinergic innervation and orexin effect observed in different motor structures must be related to the different functional roles of the orexin system in those structures, and consequently fulfill the functional relevance of orexin system in the central motor control. On the other hand, it has been suggested that the orexin system receives different types of information about the external/internal environments (Routh, 2002; Yamanaka et al., 2003; Acuna-Goycolea and van den Pol, 2004; Burdakov et al., 2005; Sakurai et al., 2005; Yoshida et al., 2006; Huang et al., 2007; Hara et al., 2009; Burt et al., 2011; Karnani et al., 2011a,b; Venner et al., 2011) and thus operate as an integrator in homeostatic physiological functions (Berthoud and Münzberg, 2011; de Lecea, 2012; Gao and Horvath, 2014; Li et al., 2014; Mahler et al., 2014). Interestingly, the output fibers of the LVN have been demonstrated to reach hypothalamic orexinergic neurons (Horowitz et al., 2005). The cerebellar–hypothalamus projections are also found and LH is one of targets of these projections (Dietrichs, 1984; Haines et al., 1997), although the targeted neurons in LH are still not identified. Moreover, the increased discharge in the orexinergic neurons (Mileykovskiy et al., 2005; Torterolo et al., 2011) and elevated orexin release (Kiyashchenko et al., 2002; Wu et al., 2002) during the obvious voluntary movements have been reported. As a result, it is reasonable to propose that the orexin system is

50


Fig. 2. A model of the connection between the orexin system and central motor control and a specific sub-module concerning the lateral vestibular nucleus from the present knowledge. The orexinergic neurons have been proved to be heterogeneous. Together with the differential modulation of orexin system on various motor control structures, we hence hypothesize that the orexinergic innervation of different motor control structures originates from different subgroups of orexinergic neurons. Additionally, some motor control structures such as the brain stem motor nuclei and cerebellum (indicated in text) have been found to send motor information back to the orexin system. In this regard, there is a substantial connection between the orexin system and the central motor control. It is said that through integrating the motor control related and other homeostatic physiological information and playing different functional roles in different motor structures, the orexin system may thus play a role in orchestrating the central motor control in a homeostatic regulation manner. As a proof, we further present a specific sub-module concerning the lateral vestibular nucleus (LVN) from the present knowledge. It has been demonstrated that orexinergic neurons send fibers to directly excite LVN neurons and vice versa. Through the reciprocal innervation, a positive feedback circuit between the orexin system and LVN is formed. The positive feedback is activated when needed (i.e., facing a major motor challenge as indicated in text), so the activity of LVN neurons can increase quickly to a robust level. This mechanism fulfills the support for the promotion of balance and postural motor activities. Meanwhile, other types of information about the external/internal environments are also conveyed to the orexin system, so as to prevent overactivity. Note that other kinds of sub-module concerning various motor control structures may also exist besides the specific one presented here.

involved in the integration of motor control related information. Through integrating the motor control related and other homeostatic physiological information, and playing different functional roles in different motor structures, the orexin system may thus play a role in orchestrating the central motor control in a homeostatic regulation manner (Fig. 2). In support of the proposal, several prominent deficits in motor activity are implicated in narcolepsy, which is caused by the loss of orexins in humans and animals. These deficits include cataplexy (Chemelli et al., 1999) and RBDnc (Dauvilliers et al., 2013). Interestingly, cataplexy and RBDnc are characterized by the sudden loss of muscle tone in wakefulness and the loss of muscle atonia in REM sleep, respectively (Chemelli et al., 1999; Dauvilliers et al., 2013). In another word, both the cataplexy and RBDnc are pathological states in which the normal motor control cannot be maintained homeostatically, highlighting a consistency with our proposal. Although the pathophysiology of the cataplexy and RBDnc is complicated, a recent clinical investigation reported that cataplexy in narcolepsy and RBDnc are specifically associated with the orexin deficiency instead of other bias factors (Knudsen et al., 2010). These results thus raise a strong possibility that cataplexy and RBDnc have importantly direct relationship with the orexin system independent of other brain functions that are influenced by the orexin system.

4.3. The significance of the regulation on central motor control by orexin system at the behavioral level As discussed in earlier sections, the cataplexy and RBDnc symptoms have prominently reflected the role of orexin system in motor activity in the context of sleep/wake states. That is to say, the orexin system’s homeostatic regulation on central motor control is involved in orchestrating the normal sleep/wake behavior. Actually, it is obvious that every kind of individual behavior consists of many aspects including the corresponding motor activity. Therefore, individual behaviors relating with the orexin system may all need the support of its homeostatic regulation on central motor control. Furthermore, the consequent influence on motor activity from this regulation should be integrated into the entirety of role for orexin system in these behaviors. Thus the homeostatic regulation of orexin system on central motor control must have coordinated relationships with its effects on other brain functions to further orchestrate individual behaviors (see Fig. 3). The role of orexin system in sleep/wake behavior is a well-documented example. On the one hand, the orexin system can actively modulate sleep/wake-related brain regions. Interestingly, through this mechanism, the indirect regulation on central motor control by orexin system, besides its direct regulation on sleep/wake states, has been


Fig. 3. A scheme of the role for orexin system concerning its regulations on central motor control and other brain functions in individual behaviors. Through the direct innervation on related brain structures, the orexin system is involved in multifaceted brain functions including the central motor control discussed here. Obviously, orexin system participates in related behaviors through regulating these brain functions. Interestingly, every kind of individual behavior consists of many aspects including the corresponding motor activity. Therefore, regulations of the orexin system on various brain functions including the central motor control must be coordinated to support its role in related behaviors, such as the sleep/wake, emotion, and energy homeostasis behaviors. The underlying mechanisms may involve the orexin system itself and/or the possible connection between related brain structures. An excellent example that has been discussed in text is from the role of orexin system in sleep/wake behavior and the connection between the sleep/wake related brain regions and motor control structures. This scheme further suggests that the significance of the homeostasis regulation on central motor control by the orexin system is beyond the pure motor activity level, but at the complex behavioral level.

extensively reviewed (Sakurai, 2003; Siegel, 2004a; de Lecea and Sutcliffe, 2005; Jones, 2008; Sinton, 2011; Dauvilliers et al., 2014). On the other hand, besides the notion of the direct influence of orexin system on motor activity in the context of sleep/wake states proposed here by us, some authors have suggested that the orexin system can promote wakefulness through enhancing locomotion activity (Anaclet et al., 2009; Sinton, 2011). In a word, the coordination between the regulation of orexin system on sleep/wake states and central motor control substantially happens. Moreover, we propose that the role of orexin system in the emotion or energy homeostasis behaviors may also be the case. It is strongly supported by the facts that many aspects of these behaviors, including the motor activity such as the defensive, avoidance, reward, seeking, feeding, or expenditure movements, are under the influence of the orexin system (for reviews, see: Boutrel, 2008; Teske et al., 2008, 2010; Kotz et al., 2008; Garland et al., 2011; Teske and Mavanji, 2012; McNally, 2014; Messina et al., 2014; Sakurai, 2014). It is further said that the homeostatic regulation of orexin system on central motor control should be paid more attentions and investigated more widely for clarifying the significance of orexin system beyond the pure motor activity level, but at the complex behavioral level. 5. Conclusion and perspectives In conclusion, the broad distribution of orexinergic fibers and receptors in central motor control structures assures the direct

51

modulations of the orexin system in various motor control subsystems. Through these direct modulations, the orexin system actively participates in the central motor control. Particularly, ascending and descending orexinergic projections exhibit the tonic and phasic modulations, respectively. Related functional relevance on the central motor control is consequently determined. Furthermore, combining the analysis of the connection between the orexin system and central motor control, a homeostatic regulation manner employed by the orexin system to orchestrate the central motor control emerges. Importantly, it is interesting to note that the symptoms of both cataplexy in narcolepsy and RBDnc are actually present in respectively specific circumstances, i.e., in a phasic manner (Chemelli et al., 1999; Siegel, 2004b; Dauvilliers et al., 2013). Hence, the importance of the orexin system’s phasic modulation on related central motor control structures is highlighted. Furthermore, our proposed model suggests that the homeostatic regulation manner employed by the orexin system to orchestrate the central motor control must underlie the core of the relationship between the orexin system’s phasic modulation and the present of cataplexy/RBDnc. Last but not least, in a scheme regarding the role of orexin system in individual behaviors, the homeostatic regulation of orexin system on central motor control is thought to coordinate with its effects on other brain functions. However, to understand the details, a series of questions still remain unsettled and urge further studies. We list the questions as follows: (1) What is the exact anatomical relationship between subgroups of orexinergic neurons and various motor control structures? (2) What kinds of motor control related information are transducted to the orexin system? (3) How are they transducted to the orexin system? (4) What kinds of other homeostatic information are integrated with these motor control related information by the orexin system and how does this integration happen? (5) Finally, in the functional aspects, it is still unknown how and to what extent these processes are used by the orexin system to orchestrate the motor control, and then the individual behaviors. What’s more, other issues should also be noted. It is unknown whether the phasic characteristic of the orexin system’s effects on related motor structures highlights the entirety of the functional significance of the orexin system in motor control. If not, are there other kinds of characteristics of the orexin system’s effects on motor structures and motor control? Ultimately, more attentions should be paid to the exact connection between these characteristics including the phasic one and the homeostatic regulation manner of the orexin system on the central motor control.

Acknowledgements This work was supported by grant 31271166 from the National Natural Science Foundation of China; grant cstc2012jjA0405 from the Chongqing Natural Science Foundation; grant 2011XQN63 from the Youth Project of Third Military Medical University.

References Acuna-Goycolea, C., van den Pol, A., 2004. Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J. Neurosci. 24, 8141–8152. Adamantidis, A., de Lecea, L., 2009. The hypocretins as sensors for metabolism and arousal. J. Physiol. 587, 33–40. Anaclet, C., Parmentier, R., Ouk, K., Guidon, G., Buda, C., Sastre, J.P., Akaoka, H., Sergeeva, O.A., Yanagisawa, M., Ohtsu, H., Franco, P., Haas, H.L., Lin, J.S., 2009. Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J. Neurosci. 29, 14423–14438. Anderson, K.N., Vincent, A., Smith, I.E., Shneerson, J.M., 2010. Cerebrospinal fluid hypocretin levels are normal in idiopathic REM sleep behaviour disorder. Eur. J. Neurol. 17, 1105–1107. Aston-Jones, G., Smith, R.J., Moorman, D.E., Richardson, K.A., 2009. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 56 (Suppl. 1), 112–121.

52


Aston-Jones, G., Smith, R.J., Sartor, G.C., Moorman, D.E., Massi, L., Tahsili-Fahadan, P., Richardson, K.A., 2010. Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res. 1314, 74–90. Badami, V.M., Rice, C.D., Lois, J.H., Madrecha, J., Yates, B.J., 2010. Distribution of hypothalamic neurons with orexin (hypocretin) or melanin concentrating hormone (MCH) immunoreactivity and multisynaptic connections with diaphragm motoneurons. Brain Res. 1323, 119–126. Baldo, B.A., Daniel, R.A., Berridge, C.W., Kelley, A.E., 2003. Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J. Comp. Neurol. 464, 220–237. Baldo, B.A., Gual-Bonilla, L., Sijapati, K., Daniel, R.A., Landry, C.F., Kelley, A.E., 2004. Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur. J. Neurosci. 19, 376–386. Bayer, L., Serafin, M., Eggermann, E., Saint-Mleux, B., Machard, D., Jones, B.E., 2004. Exclusive postsynaptic action of hypocretin–orexin on sublayer 6b cortical neurons. J. Neurosci. 24, 6760–6764. Berthoud, H.R., Münzberg, H., 2011. The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to optogenetics. Physiol. Behav. 104, 29–39. Boutrel, B., 2008. A neuropeptide-centric view of psychostimulant addiction. Br. J. Pharmacol. 154, 343–357. Burdakov, D., Gerasimenko, O., Verkhratsky, A., 2005. Physiological changes in glucose differentially modulate the excitability of hypothalamic melaninconcentrating hormone and orexin neurons in situ. J. Neurosci. 25, 2429–2433. Burt, J., Alberto, C.O., Parsons, M.P., Hirasawa, M., 2011. Local network regulation of orexin neurons in the lateral hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R572–R580. Büttner-Ennever, J.A., 2006. The extraocular motor nuclei: organization and functional neuroanatomy. Prog. Brain Res. 151, 95–125. Büttner-Ennever, J.A., Horn, A.K., Scherberger, H., D’Ascanio, P., 2001. Motoneurons of twitch and nontwitch extraocular muscle fibers in the abducens, trochlear, and oculomotor nuclei of monkeys. J. Comp. Neurol. 438, 318–335. Cason, A.M., Smith, R.J., Tahsili-Fahadan, P., Moorman, D.E., Sartor, G.C., Aston-Jones, G., 2010. Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol. Behav. 100, 419–428. Chee, P.H., 1968. Ocular manifestations of narcolepsy. Br. J. Ophthalmol. 52, 54–56. Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B., Yanagisawa, M., 1999. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451. Chen, Q., de Lecea, L., Hu, Z., Gao, D., 2014. The hypocretin/orexin system: an increasingly important role in neuropsychiatry. Med. Res. Rev., http://dx.doi.org/10.1002/med.21326. Chen, H., Yang, L., Chen, F., Yan, J., Yang, N., Wang, Y.J., Zhu, Z.R., Hu, Z.A., Sui, J.F., Hu, B., 2013. Functional inactivation of orexin 1 receptors in the cerebellum disrupts trace eyeblink conditioning and local theta oscillations in guinea pigs. Behav. Brain Res. 250, 114–122. Clancy, B., Cauller, L.J., 1999. Widespread projections from subgriseal neurons (layer VII) to layer I in adult rat cortex. J. Comp. Neurol. 407, 275–286. Cluderay, J.E., Harrison, D.C., Hervieu, G.J., 2002. Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul. Pept. 104, 131–144. Cutler, D.J., Morris, R., Sheridhar, V., Wattam, T.A., Holmes, S., Patel, S., Arch, J.R., Wilson, S., Buckingham, R.E., Evans, M.L., Leslie, R.A., Williams, G., 1999. Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 20, 1455–1470. D’Angelo, E., Mazzarello, P., Prestori, F., Mapelli, J., Solinas, S., Lombardo, P., Cesana, E., Gandolfi, D., Congi, L., 2011. The cerebellar network: from structure to function and dynamics. Brain Res. Rev. 66, 5–15. D’Angelo, E., Nieus, T., Maffei, A., Armano, S., Rossi, P., Taglietti, V., Fontana, A., Naldi, G., 2001. Theta-frequency bursting and resonance in cerebellar granule cells: experimental evidence and modeling of a slow k+ -dependent mechanism. J. Neurosci. 21, 759–770. Dalal, J., Roh, J.H., Maloney, S.E., Akuffo, A., Shah, S., Yuan, H., Wamsley, B., Jones, W.B., de Guzman Strong, C., Gray, P.A., Holtzman, D.M., Heintz, N., Dougherty, J.D., 2013. Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation. Genes Dev. 27, 565–578. Date, Y., Mondal, M.S., Matsukura, S., Nakazato, M., 2000. Distribution of orexinA and orexin-B (hypocretins) in the rat spinal cord. Neurosci. Lett. 288, 87–90. Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M., Nakazato, M., 1999. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc. Natl. Acad. Sci. U. S. A. 96, 748–753. Dauvilliers, Y., Jennum, P., Plazzi, G., 2013. Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy. Sleep Med. 14, 775–781. Dauvilliers, Y., Siegel, J.M., Lopez, R., Torontali, Z.A., Peever, J.H., 2014. Cataplexy – clinical aspects, pathophysiology and management strategy. Nat. Rev. Neurol. 10, 386–395. de Lecea, L., 2012. Hypocretins and the neurobiology of sleep–wake mechanisms. Prog. Brain Res. 198, 15–24.

de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X., Foye, P.E., Danielson, P.E., Fukuhara, C., Battenberg, E.L., Gautvik, V.T., Bartlett 2nd, F.S., Frankel, W.N., van den Pol, A.N., Bloom, F.E., Gautvik, K.M., Sutcliffe, J.G., 1998. The hypocretins: hypothalamusspecific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U. S. A. 95, 322–327. de Lecea, L., Sutcliffe, J.G., 2005. The hypocretins and sleep. FEBS J. 272, 5675–5688. De Zeeuw, C.I., Yeo, C.H., 2005. Time and tide in cerebellar memory formation. Curr. Opin. Neurobiol. 15, 667–674. Dietrichs, E., 1984. Cerebellar autonomic function: direct hypothalamocerebellar pathway. Science 223, 591–593. ˜ R.A., McCormack, S.L., Mochizuki, T., Scammell, T.E., 2007. Running proEspana, motes wakefulness and increases cataplexy in orexin knockout mice. Sleep 30, 1417–1425. Fenik, V.B., Rukhadze, I., Kubin, L., 2009. Antagonism of alpha1-adrenergic and serotonergic receptors in the hypoglossal motor nucleus does not prevent motoneuronal activation elicited from the posterior hypothalamus. Neurosci. Lett. 462, 80–84. Friston, K., 2011. What is optimal about motor control? Neuron 72, 488–498. Fung, S.J., Yamuy, J., Sampogna, S., Morales, F.R., Chase, M.H., 2001. Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: a doublelabeling immunohistochemical study. Brain Res. 903, 257–262. Gandolfi, D., Lombardo, P., Mapelli, J., Solinas, S., D’Angelo, E., 2013. ␪-Frequency resonance at the cerebellum input stage improves spike timing on the millisecond time-scale. Front. Neural Circuits 7, 64. Gao, X.B., Horvath, T.L., 2011. An arousing discovery on catalepsy: orexin regulates vestibular motor functions. Neuron 69, 588–590. Gao, X.B., Horvath, T., 2014. Function and dysfunction of hypocretin/orexin: an energetics point of view. Annu. Rev. Neurosci. 37, 101–116. Garland Jr., T., Schutz, H., Chappell, M.A., Keeney, B.K., Meek, T.H., Copes, L.E., Acosta, W., Drenowatz, C., Maciel, R.C., van Dijk, G., Kotz, C.M., Eisenmann, J.C., 2011. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J. Exp. Biol. 214, 206–229. Gautvik, K.M., de Lecea, L., Gautvik, V.T., Danielson, P.E., Tranque, P., Dopazo, A., Bloom, F.E., Sutcliffe, J.G., 1996. Overview of the most prevalent hypothalamusspecific mRNAs, as identified by directional tag PCR subtraction. Proc. Natl. Acad. Sci. U. S. A. 93, 8733–8738. Greco, M.A., Shiromani, P.J., 2001. Hypocretin receptor protein and mRNA expression in the dorsolateral pons of rats. Brain Res. Mol. Brain Res. 88, 176–182. Haines, D.E., Dietrichs, E., Mihailoff, G.A., McDonald, E.F., 1997. The cerebellar–hypothalamic axis: basic circuits and clinical observations. Int. Rev. Neurobiol. 41, 83–107. Hara, J., Beuckmann, C.T., Nambu, T., Willie, J.T., Chemelli, R.M., Sinton, C.M., Sugiyama, F., Yagami, K., Goto, K., Yanagisawa, M., Sakurai, T., 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354. Hara, J., Gerashchenko, D., Wisor, J.P., Sakurai, T., Xie, X., Kilduff, T.S., 2009. Thyrotropin-releasing hormone increases behavioral arousal through modulation of hypocretin/orexin neurons. J. Neurosci. 29, 3705–3714. Harris, G.C., Aston-Jones, G., 2006. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 29, 571–577. Hervieu, G.J., Cluderay, J.E., Harrison, D.C., Roberts, J.C., Leslie, R.A., 2001. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103, 777–797. Hoffmann, L.C., Berry, S.D., 2009. Cerebellar theta oscillations are synchronized during hippocampal theta-contingent trace conditioning. Proc. Natl. Acad. Sci. U. S. A. 106, 21371–21376. Horowitz, S.S., Blanchard, J., Morin, L.P., 2005. Medial vestibular connections with the hypocretin (orexin) system. J. Comp. Neurol. 487, 127–146. Huang, H., Acuna-Goycolea, C., Li, Y., Cheng, H.M., Obrietan, K., van den Pol, A.N., 2007. Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal. J. Neurosci. 27, 4870–4881. Ito, M., 2009. Functional roles of neuropeptides in cerebellar circuits. Neuroscience 162, 666–672. Johnson, P.L., Molosh, A., Fitz, S.D., Truitt, W.A., Shekhar, A., 2012. Orexin, stress, and anxiety/panic states. Prog. Brain Res. 198, 133–161. Jones, B.E., 2008. Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems. Ann. N. Y. Acad. Sci. 1129, 26–34. Karnani, M.M., Apergis-Schoute, J., Adamantidis, A., Jensen, L.T., de Lecea, L., Fugger, L., Burdakov, D., 2011a. Activation of central orexin/hypocretin neurons by dietary amino acids. Neuron 72, 616–629. Karnani, M.M., Venner, A., Jensen, L.T., Fugger, L., Burdakov, D., 2011b. Direct and indirect control of orexin/hypocretin neurons by glycine receptors. J. Physiol. 589, 639–651. Kiyashchenko, L.I., Mileykovskiy, B.Y., Maidment, N., Lam, H.A., Wu, M.F., John, J., Peever, J., Siegel, J.M., 2002. Release of hypocretin (orexin) during waking and sleep states. J. Neurosci. 22, 5282–5286. Knudsen, S., Gammeltoft, S., Jennum, P., 2010. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency. Brain 133, 568–579. Korotkova, T.M., Eriksson, K.S., Haas, H.L., Brown, R.E., 2002. Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul. Pept. 104, 83–89. Kotz, C.M., 2006. Integration of feeding and spontaneous physical activity: role for orexin. Physiol. Behav. 88, 294–301.

B. Hu et al. / Neuroscience and Biobehavioral Reviews 49 (2015) 43–54 Kotz, C.M., Teske, J.A., Billington, C.J., 2008. Neuroregulation of nonexercise activity thermogenesis and obesity resistance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 94, 699–710. Kotz, C.M., Wang, C., Teske, J.A., Thorpe, A.J., Novak, C.M., Kiwaki, K., Levine, J.A., 2006. Orexin A mediation of time spent moving in rats: neural mechanisms. Neuroscience 142, 29–36. Kukkonen, J.P., 2013. Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am. J. Physiol. Cell Physiol. 304, C2–C32. Kukkonen, J.P., Holmqvist, T., Ammoun, S., Akerman, K.E., 2002. Functions of the orexinergic/hypocretinergic system. Am. J. Physiol. Cell Physiol. 283, C1567–C1591. Lambe, E.K., Aghajanian, G.K., 2003. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40, 139–150. Lee, H.S., Park, S.H., Song, W.C., Waterhouse, B.D., 2005. Retrograde study of hypocretin-1 (orexin-A) projections to subdivisions of the dorsal raphe nucleus in the rat. Brain Res. 1059, 35–45. Li, J., Hu, Z., de Lecea, L., 2014. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350. Mahler, S.V., Moorman, D.E., Smith, R., James, M.H., Aston-Jones, G., 2014. Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat. Neurosci. 17, 1298–1303. Mahler, S.V., Smith, R.J., Moorman, D.E., Sartor, G.C., Aston-Jones, G., 2012. Multiple roles for orexin/hypocretin in addiction. Prog. Brain Res. 198, 79–121. Manto, M., Oulad Ben Taib, N., 2010. Cerebellar nuclei: key roles for strategically located structures. Cerebellum 9, 17–21. Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M., Elmquist, J.K., 2001. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25. Mascaro, M.B., Prosdócimi, F.C., Bittencourt, J.C., Elias, C.F., 2009. Forebrain projections to brainstem nuclei involved in the control of mandibular movements in rats. Eur. J. Oral Sci. 117, 676–684. Matsuki, T., Sakurai, T., 2008. Orexins and orexin receptors: from molecules to integrative physiology. Results Probl. Cell Differ. 46, 27–55. McGregor, R., Damián, A., Fabbiani, G., Torterolo, P., Pose, I., Chase, M., Morales, F.R., 2005. Direct hypothalamic innervation of the trigeminal motor nucleus: a retrograde tracer study. Neuroscience 136, 1073–1081. McNally, G.P., 2014. Extinction of drug seeking: neural circuits and approaches to augmentation. Neuropharmacology 76, 528–532. Medina, J.F., Mauk, M.D., 2000. Computer simulation of cerebellar information processing. Nat. Neurosci. 3 (Suppl.), 1205–1211. Messina, G., Dalia, C., Tafuri, D., Monda, V., Palmieri, F., Dato, A., Russo, A., De Blasio, S., Messina, A., De Luca, V., Chieffi, S., Monda, M., 2014. Orexin-A controls sympathetic activity and eating behavior. Front. Psychol. 5, 997. Mieda, M., Sakurai, T., 2012. Overview of orexin/hypocretin system. Prog. Brain Res. 198, 5–14. Mieda, M., Willie, J.T., Hara, J., Sinton, C.M., Sakurai, T., Yanagisawa, M., 2004. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuronablated model of narcolepsy in mice. Proc. Natl. Acad. Sci. U. S. A. 101, 4649–4654. Mileykovskiy, B.Y., Kiyashchenko, L.I., Siegel, J.M., 2002. Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla. J. Neurophysiol. 87, 2480–2489. Mileykovskiy, B.Y., Kiyashchenko, L.I., Siegel, J.M., 2005. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46, 787–798. Mochizuki, T., Crocker, A., McCormack, S., Yanagisawa, M., Sakurai, T., Scammell, T.E., 2004. Behavioral state instability in orexin knock-out mice. J. Neurosci. 24, 6291–6300. Moore, M.W., Akladious, A., Hu, Y., Azzam, S., Feng, P., Strohl, K.P., 2014. Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse. Respir. Physiol. Neurobiol. 200, 118–125. Morganstern, I., Chang, G.Q., Barson, J.R., Ye, Z., Karatayev, O., Leibowitz, S.F., 2010. Differential effects of acute and chronic ethanol exposure on orexin expression in the perifornical lateral hypothalamus. Alcohol. Clin. Exp. Res. 34, 886–896. Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M., Goto, K., 1999. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260. Nardone, R., Bergmann, J., Kunz, A., Caleri, F., Seidl, M., Tezzon, F., Gerstenbrand, F., Trinka, E., Golaszewski, S., 2011. Cortical excitability changes in patients with sleep–wake disturbances after traumatic brain injury. J. Neurotrauma 28, 1165–1171. Nisimaru, N., Mittal, C., Shirai, Y., Sooksawate, T., Anandaraj, P., Hashikawa, T., Nagao, S., Arata, A., Sakurai, T., Yamamoto, M., Ito, M., 2013. Orexin-neuromodulated cerebellar circuit controls redistribution of arterial blood flows for defense behavior in rabbits. Proc. Natl. Acad. Sci. U. S. A. 110, 14124–14131. Ohno, K., Sakurai, T., 2008. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front. Neuroendocrinol. 29, 70–87. Oliviero, A., Della Marca, G., Tonali, P.A., Pilato, F., Saturno, E., Dileone, M., Versace, V., Mennuni, G., Di Lazzaro, V., 2005. Functional involvement of cerebral cortex in human narcolepsy. J. Neurol. 252, 56–61. Peever, J.H., Lai, Y.Y., Siegel, J.M., 2003. Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J. Neurophysiol. 89, 2591–2600. Peyron, C., Tighe, D.K., van den Pol, A.N., de Lecea, L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S., 1998. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015.

53

Pinos, H., Pérez-Izquierdo, M.A., Carrillo, B., Collado, P., 2011. Effects of undernourishment on the hypothalamic orexinergic system. Physiol. Behav. 102, 17–21. Rasmussen, K., Hsu, M.A., Yang, Y., 2007. The orexin-1 receptor antagonist SB334867 blocks the effects of antipsychotics on the activity of A9 and A10 dopamine neurons: implications for antipsychotic therapy. Neuropsychopharmacology 32, 786–792. Reep, R.L., 2000. Cortical layer VII and persistent subplate cells in mammalian brains. Brain Behav. Evol. 56, 212–234. Richardson, K.A., Aston-Jones, G., 2012. Lateral hypothalamic orexin/hypocretin neurons that project to ventral tegmental area are differentially activated with morphine preference. J. Neurosci. 2012 (32), 3809–3817. Rosin, D.L., Weston, M.C., Sevigny, C.P., Stornetta, R.L., Guyenet, P.G., 2003. Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J. Comp. Neurol. 465, 593–603. Routh, V.H., 2002. Glucose-sensing neurons: are they physiologically relevant? Physiol. Behav. 76, 403–413. Sakurai, T., 2003. Orexin: a link between energy homeostasis and adaptive behaviour. Curr. Opin. Clin. Nutr. Metab. Care 6, 353–360. Sakurai, T., 2007. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat. Rev. Neurosci. 8, 171–181. Sakurai, T., 2014. The role of orexin in motivated behaviours. Nat. Rev. Neurosci. 15, 719–731. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richarson, J.A., Kozlowski, G.P., Wilson, S., Arch, J.R., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNulty, D.E., Liu, W.S., Terrett, J.A., Elshourbagy, N.A., Bergsma, D.J., Yanagisawa, M., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. Sakurai, T., Nagata, R., Yamanaka, A., Kawamura, H., Tsujino, N., Muraki, Y., Kageyama, H., Kunita, S., Takahashi, S., Goto, K., Koyama, Y., Shioda, S., Yanagisawa, M., 2005. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46, 297–308. Schöne, C., Venner, A., Knowles, D., Karnani, M.M., Burdakov, D., 2011. Dichotomous cellular properties of mouse orexin/hypocretin neurons. J. Physiol. 589, 2767–2779. Schreyer, S., Büttner-Ennever, J.A., Tang, X., Mustari, M.J., Horn, A.K., 2009. Orexin-A inputs onto visuomotor cell groups in the monkey brainstem. Neuroscience 164, 629–640. Shin, H.S., Cho, H.S., Sung, K.W., Yoon, B.J., 2009. Orexin-A increases cell surface expression of AMPA receptors in the striatum. Biochem. Biophys. Res. Commun. 378, 409–413. Siegel, J.M., 2004a. The neurotransmitters of sleep. J. Clin. Psychiatry 65 (Suppl. 16), 4–7. Siegel, J.M., 2004b. Hypocretin (orexin): role in normal behavior and neuropathology. Annu. Rev. Psychol. 55, 125–148. Sinton, C.M., 2011. Orexin/hypocretin plays a role in the response to physiological disequilibrium. Sleep Med. Rev. 15, 197–207. Stoyanova, I.I., Lazarov, N.E., 2005. Localization of orexin-A-immunoreactive fibers in the mesencephalic trigeminal nucleus of the rat. Brain Res. 1054, 82–87. Surendran, S., Campbell, G.A., Tyring, S.K., Matalon, K., McDonald, J.D., Matalon, R., 2003. High levels of orexin A in the brain of the mouse model for phenylketonuria: possible role of orexin A in hyperactivity seen in children with PKU. Neurochem. Res. 28, 1891–1894. Sutcliffe, J.G., de Lecea, L., 2002. The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349. Taheri, S., Mahmoodi, M., Opacka-Juffry, J., Ghatei, M.A., Bloom, S.R., 1999. Distribution and quantification of immunoreactive orexin A in rat tissues. FEBS. Lett. 457, 157–161. Takakusaki, K., Takahashi, K., Saitoh, K., Harada, H., Okumura, T., Kayama, Y., Koyama, Y., 2005. Orexinergic projections to the cat midbrain mediate alternation of emotional behavioural states from locomotion to cataplexy. J. Physiol. 568, 1003–1020. Tarasiuk, A., Levi, A., Berdugo-Boura, N., Yahalom, A., Segev, Y., 2014. Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats. Sleep 37, 987–998. Teske, J.A., Billington, C.J., Kotz, C.M., 2008. Neuropeptidergic mediators of spontaneous physical activity and non-exercise activity thermogenesis. Neuroendocrinology 87, 71–90. Teske, J.A., Billington, C.J., Kotz, C.M., 2010. Hypocretin/orexin and energy expenditure. Acta Physiol. (Oxf.) 198, 303–312. Teske, J.A., Mavanji, V., 2012. Energy expenditure: role of orexin. Vitam. Horm. 89, 91–109. Trivedi, P., Yu, H., MacNeil, D.J., van der Ploeg, L.H., Guan, X.M., 1998. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75. Torterolo, P., Ramos, O.V., Sampogna, S., Chase, M.H., 2011. Hypocretinergic neurons are activated in conjunction with goal-oriented survival-related motor behaviors. Physiol. Behav. 104, 823–830. van den Pol, A.N., 1999. Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J. Neurosci. 19, 3171–3182. Venner, A., Karnani, M.M., Gonzalez, J.A., Jensen, L.T., Fugger, L., Burdakov, D., 2011. Orexin neurons as conditional glucosensors: paradoxical regulation of sugar sensing by intracellular fuels. J. Physiol. 589, 5701–5708. Wikgren, J., Nokia, M.S., Penttonen, M., 2010. Hippocampo-cerebellar theta band phase synchrony in rabbits. Neuroscience 165, 1538–1545.

54


Williams, R.H., Alexopoulos, H., Jensen, L.T., Fugger, L., Burdakov, D., 2008. Adaptive sugar sensors in hypothalamic feeding circuits. Proc. Natl. Acad. Sci. U. S. A. 105, 11975–11980. Williams, R.H., Burdakov, D., 2008. Hypothalamic orexins/hypocretins as regulators of breathing. Expert Rev. Mol. Med. 10, e28. Williams, R.H., Morton, A.J., Burdakov, D., 2011. Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington’s disease. Neurobiol. Dis. 42, 438–445. Willie, J.T., Lim, M.M., Bennett, R.E., Azarion, A.A., Schwetye, K.E., Brody, D.L., 2012. Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice. J. Neurotrauma 29, 1908–1921. Wu, M.F., John, J., Maidment, N., Lam, H.A., Siegel, J.M., 2002. Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R1079–R1086. Yamanaka, A., Beuckmann, C.T., Willie, J.T., Hara, J., Tsujino, N., Mieda, M., Tominaga, M., Yagami, Ki., Sugiyama, F., Goto, K., Yanagisawa, M., Sakurai, T., 2003. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713. Yamuy, J., Fung, S.J., Xi, M., Chase, M.H., 2004. Hypocretinergic control of spinal cord motoneurons. J. Neurosci. 24, 5336–5345.

Yamuy, J., Fung, S.J., Xi, M., Chase, M.H., 2010. State-dependent control of lumbar motoneurons by the hypocretinergic system. Exp. Neurol. 221, 335–345. ˜ R.A., Crocker, A., Scammell, T.E., 2006. Afferents Yoshida, K., McCormack, S., Espana, to the orexin neurons of the rat brain. J. Comp. Neurol. 494, 845–861. Young, J.K., Wu, M., Manaye, K.F., Kc, P., Allard, J.S., Mack, S.O., Haxhiu, M.A., 2005. Orexin stimulates breathing via medullary and spinal pathways. J. Appl. Physiol. (1985) 98, 1387–1395. Yu, L., Zhang, X.Y., Zhang, J., Zhu, J.N., Wang, J.J., 2010. Orexins excite neurons of the rat cerebellar nucleus interpositus via orexin 2 receptors in vitro. Cerebellum 9, 88–95. Zhang, J., Li, B., Yu, L., He, Y.C., Li, H.Z., Zhu, J.N., Wang, J.J., 2011. A role for orexin in central vestibular motor control. Neuron 69, 793–804. Zhang, J., Luo, P., 2002. Orexin B immunoreactive fibers and terminals innervate the sensory and motor neurons of jaw-elevator muscles in the rat. Synapse 44, 106–110. Zhang, X.Y., Yu, L., Zhuang, Q.X., Zhang, J., Zhu, J.N., Wang, J.J., 2013. Hypothalamic histaminergic and orexinergic modulation on cerebellar and vestibular motor control. Cerebellum 12, 294–296.

Does the motor system need intermittent control?

Developmental kinesiology: three levels of motor control in the assessment and treatment of the motor system.

The frontoparietal control system: a central role in mental health.

Roles of Hox genes in the patterning of the central nervous system of Drosophila.

The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity.

The expression and roles of Nde1 and Ndel1 in the adult mammalian central nervous system.

hypocretin neurones and the histaminergic system.

Involvement of the orexin system in sympathetic nerve regulation.

Opposing Roles of Interferon-Gamma on Cells of the Central Nervous System in Autoimmune Neuroinflammation.

orexin system: an increasingly important role in neuropsychiatry.

Differential roles of microglia and monocytes in the inflamed central nervous system.

The orexin system in the enteric nervous system of the bottlenose dolphin (Tursiops truncatus).

orexin system mediates the extinction of fear memories.

hypocretin system and autonomic control: new insights and clinical correlations.

Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.

Is an inventory control system needed in central service?

The role of the cholinergic system in the central control of thermoregulation in rats.

Control of excitability and threshold in the thalamocortical motor system of the cat by cerebellar stimulation.

Orexin Neuronal System: An Unexpectedly Productive Journey.

Control of cutaneous blood flow by central nervous system.

Long-term control of central nervous system leukaemia.

Blocking central pathways in the primate motor system using high-frequency sinusoidal current.

Orexin System: The Key for a Healthy Life.

Central actions of angiotensin in cardiovascular control: multiple roles for a single peptide.