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Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding regulation

Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding... BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu008 Review Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding regulation Liam Anuj O’Leary Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK *Corresponding author: Email: zcbthj2@ucl.ac.uk Project Supervisor: Dr Jason Rihel, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Tel: +44 020 3549 5508. Email: j.rihel@ucl.ac.uk Orexin and melanin-concentrating hormone (MCH) neurons reside in the lateral hypothalamic area (LHA) and regulate sleep and feeding behaviour in mammals. In rodents, orexin neurons are implicated in the regulation of wakefulness or palatable con- sumption, whereas MCH neurons are implicated in the regulation of rapid eye movement sleep episode duration or caloric con- sumption. This review explores the molecular, genetic and neuronal components of orexin and MCH signalling as mediators of arousal state transitions. These peptidergic signalling systems, which interconnect both with sleep centres in the LHA and feed- ing centres in the arcuate nucleus, may maintain the balance between sleep need and duration with hunger and food foraging. Key words: orexin, melanin-concentrating hormone, lateral hypothalamic area, arcuate nucleus, sleep, feeding Submitted on 8 April 2014; accepted on 8 September 2014 Introduction neuropeptides released from LHA principal neurons, which can cause narcolepsy in many mammalian species (Lin et al., Hypothalamic regulation of sleep 1999). Feeding regulation also involves a neuronal circuit, and feeding here described as the feeding circuit, which includes input and output regions of the arcuate nucleus (ARC). The importance Sleep and feeding are goal-directed activities which mammals of ARC neurons for feeding behaviour is demonstrated by the must perform to survive. Sleep deprivation and hunger are ablation of ARC principal neurons, which can cause fatal especially suitable for studying in animal models, as sleep and starvation in adult rats (Luquet et al., 2005). Both the AAS feeding are not evidently reliant on volition, emotion or intel- and the feeding circuit are modulated by the neuropeptide- ligence (Le Doux, 2012; Sternson, 2013). While the require- mediated activity of principal neurons in the LHA, namely ment of feeding for survival is self-evident, there is also ample orexin (also known as hypocretin) and melanin-concentrating evidence from sleep deprivation studies which indicates that hormone (MCH) neurons (see Table 1 for abbreviations). sleep is also required for mammalian survival (Rechtschaffen This review proposes that orexin and MCH neurons form sig- et al., 1983; Campbell and Tobler, 1984; Bentivoglio and nificant inputs to the AAS and the feeding circuit to enable Grassi-Zucconi, 1997). Sleep regulation involves a neuronal crosstalk between sleep and feeding regulation. circuit known as the ascending arousal system (AAS), which includes projections to the neocortex from the brainstem and Orexin: structure and signalling mechanisms subcortical nuclei such as the lateral hypothalamic area (LHA). The importance of LHA neurons for arousal There are two mammalian peptide isoforms of orexin, maintenance is demonstrated by the genetic knockout of orexin-A (OX ) and orexin-B (OX ), which are each encoded A B © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons 1 1 Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Research article Bioscience Horizons • Volume 7 2014 Table 1. Abbreviations in text and figures Symbol Definition Symbol Definition AAS Ascending arousal system MCHR1 Melanin-concentrating hormone receptor 1 ACh Acetylcholine MCHR2 Melanin-concentrating hormone receptor 1 AgRP Agouti-related peptide mEPSCs Miniature excitatory postsynaptic currents α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic AMPA mnPO Medial preoptic area acid NA Noradrenaline ARC Arcuate nucleus NEI Neuropeptide E-I BF Basal forebrain NGE Neuropeptide G-E ChR2 Channelrhodopsin-2 CSF Cerebrospinal fluid NREMS Non-rapid eye movement sleep DA Dopamine NTS Nucleus of the solitary tract dRN Dorsal raphe nucleus OX Orexin-A EEG Electroencephalography OX Orexin-B EMG Electromyography OX/ChR2 Orexin/Channelrhodopsin-2 EOG Electrooculography PAG Periaqueductal grey EPSP Excitatory postsynaptic potential PB Parabrachial nucleus GABA γ-aminobutyric acid P-LC Pre-locus coeruleus GAD Isoform 65 of glutamic acid decarboxylase Pmch Pro-melanin-concentrating hormone GAD Isoform 67 of glutamic acid decarboxylase POMC Proopiomelanocortin Glu Glutamate PPT Pedunculopontine tegmentum GPCRs G protein-coupled receptors PVH Paraventricular hypothalamus His Histamine PVT Paraventricular thalamus hMCHR1 Human melanin-concentrating hormone receptor 1 REMS Rapid eye movement sleep hMCHR2 Human melanin-concentrating hormone receptor 2 RIP-Cre Rat insulin promoter-cre hOX R Human orexin 1 receptor RPa Raphe pallidus hOX R Human orexin 2 receptor SCN Suprachiasmatic nucleus HPF Highly palatable food ICV Intracerebrovascular SLD Sublaterodorsal tegmentum LC Locus coeruleus SWS Slow-wave sleep; N3 LDT Laterodorsal tegmentum TMN Tuberomammillary nucleus LHA Lateral hypothalamic area TRPM5 Long transient receptor potential channel 5 NPY Neuropeptide Y vlPAG Ventrolateral periaqueductal grey N1 Non-rapid eye movement sleep 1; drowsy sleep vlPO Ventrolateral preoptic area N2 Non-rapid eye movement sleep 2 vPAG Ventral periaqueductal grey N3 Non-rapid eye movement sleep 3; SWS 5-HT 5-Hydroxytryptamine MCH Melanin-concentrating hormone 2 Bioscience Horizons • Volume 7 2014 Research article by one of the two exons of the prepro-orexin gene (Fig. 1 affinity for OX and OX (Sakurai et al., 1998). Orexin can A B A–B) and formed after alternative splicing of the prepro- facilitate excitatory postsynaptic potentials mediated by glu- orexin peptide in mice and humans (Miyoshi et al., 2001). tamate release from orexin neurons (Zhu et al., 2003) and Both OX and OX can bind to orexin receptor 1 (OX R) can depolarize orexin neurons ex vivo (Yamanaka et al., A B 1 and orexin receptor 2 (OX R) in vitro (Fig. 1D–E), which are 2010). Thus, orexin generally potentiates excitatory trans- G protein-coupled receptors (GPCRs) that can couple to mul- mission mediated by orexin neuronal terminals. tiple Gα-subtypes including Gα , Gα , Gα and Gα (Sakurai s i o q et al., 1998; Kim et al., 2004; Karteris et al., 2005). The MCH: structure and signalling mechanisms orexin receptors have different affinity profiles for orexin peptide isoforms (Fig. 1C): OX R is selective by one order of Human MCH is one of three neuropeptides encoded by the magnitude for OX over OX , whereas OX R has equal Pmch gene (Pedeutour, Szpirer and Nahon, 1994) and can A B 2 Figure 1. Orexin signalling. (A) Both orexin-A (OX ) and orexin-B (OX ) are encoded by a single exon of the prepro-orexin gene. (B) Unlike OX , A B B OX has two disulphide bonds (black lines). Almost half (46%, black circles) of OX peptide sequence is conserved with OX peptide sequence. A B A (C) OX and OX act via two GPCRs named OX R and OX R. OX has twice the affinity for OX R than for OX R, whereas OX has equal affinity for A B 1 2 A 1 2 B both OX R and OX R. (D) There are unique (white circles), conserved (black circles) and insertion (grey circles) regions in the peptide sequences 1 2 of human OX R (hOX R) and OX R (hOX R). (E) Potential signalling mechanisms of rat OX R/OX R. Adapted from Tsujino and Sakurai (2013). 1 1 2 2 1 2 3 Research article Bioscience Horizons • Volume 7 2014 bind to two related GPCRs (Hawes et al., 2000; Wang et al., contain mRNA for isoform 67 of glutamic acid decarboxyl- 2001), MCH receptor 1 (MCHR1) and MCH receptor 2 ase (GAD ) (Harthoorn et al., 2005; Elias et al., 2008; (MCHR2) (Fig. 2A–D). Only ‘higher order’ mammals such Rondini et al., 2010; Sapin et al., 2010), and in vitro MCH as ferrets, dogs and primates express functional MCHR2 signalling decreases the frequency of minature excitatory (Tan et al., 2002). Rodent MCHR1 utilizes primarily Gα postsynaptic potentials (mEPSCs) (Gao and van den Pol, i/o signalling but also other unidentified G α signalling path- 2001). Thus, MCH potentiates inhibitory GABAergic trans- ways (Hawes et al., 2000) (Fig. 2E). All MCH neurons mission mediated by MCH neuronal terminals (Fig. 2). Figure 2. MCH signalling. (A) The human prepro-MCH (PMCH) gene encodes neuropeptide G-E (NGE), neuropeptide E-I (NEI) and MCH. (B) NGE and NEI have no effect on MCH signalling; MCH is a non-adecapeptide containing one disulphide bond. ( C) MCH binds with relatively similar binding affinity to both MCHR1 and MCHR2. ( D) There are unique (white dots), conserved (black dots) and insertion (grey dots) sequences in the peptide sequences of human MCHR1 (hMCHR1) and MCHR2 (hMCHR2). (E) Potential signalling mechanisms of rat MCHR1, hMCHR1 and hMCHR2. 4 Bioscience Horizons • Volume 7 2014 Research article maintained by the suprachiasmatic nucleus (SCN), which Sleep regulation can be entrained by cyclic environmental cues including light exposure. Definitions of sleep and the arousal circuit: AAS Vertebrates can transition from one arousal state (wakeful- Sleep is a global state that involves major changes in behav- ness, NREMS or REMS) to another in response to changes in iour, consciousness and cognition. In mammals, sleep is activity within the AAS (Saper, Scammell and Lu, 2005). Most composed of four distinct stages defined by cortical electro - AAS regions are either wake promoting or sleep promoting, encephalography (EEG) activity: rapid-eye movement sleep with the latter class subdivided into those which promote (REMS) and three stages of non-rapid eye movement sleep REMS (REMS-on) and those which promote NREMS (NREMS) named NREMS 1 (N1), NREMS 2 (N2) and (REMS-off). The AAS is divided into thalamic and extratha- NREMS 3 (N3) sleep (Fig. 3). The timing of REMS and lamic routes (Fig. 4): pedunculopontine (PPT) and laterodor- NREMS is regulated by two general processes, homeostatic sal tegmentum (LDT) projections to the thalamus, or midbrain and circadian processes (Borbély, 1982). Homeostatic pro- projections through the reticular formation to the basal fore- cesses govern the rise of sleep pressure during wakefulness brain (BF) (Fuller and Lu, 2009). The extrathalamic system and the dissipation of sleep pressure during sleep. consists of the dorsal raphe nucleus (dRN), locus coeruleus Homeostatic processes also govern sleep rebound, which is a (LC), LHA, tuberomammillary nucleus (TMN), ventral compensatory increase in NREMS or REMS duration (vPAG) and ventrolateral (vlPAG) periaqueductal grey, and following sleep deprivation. Circadian processes govern the ventrolateral (vlPO) and medial (mnPO) preoptic nucleus sleep onset relative to an internal 24 h clock-like rhythm (see Table 1 for abbreviations). The extrathalamic route Figure 3. Sleep: polysomnography, hypnogram, orexin and MCH neuronal recordings in a healthy individual. Wakefulness involves gamma (25–80 Hz) and beta (14–25 Hz) EEG waves; conscious relaxation involves alpha (8–13 Hz) waves. There are four stages of sleep across REMS and NREMS. During NREMS 1 (N1), theta waves (4–7 Hz) predominate, accompanied with a partial loss of consciousness. During NREMS 2 (N2), sleep spindles (series of 11–16 Hz waves which are usually maximal nearest the median wave) and K-complexes (sharp bi- or tri-phasic waveforms) predominate. During NREMS 3 (N3), also known as slow-wave sleep, slow, high amplitude delta (0–4 Hz) waves predominate. During REMS (grey column), also known as paradoxical sleep as (desynchronized) waves resemble wakefulness, distinct sawtooth wave (serrated 2–6 Hz waves), rapid eye movements (EOG) and motor atonia (EMG) recordings appear. Orexin neurons are active only during wakefulness. MCH neurons are active only during sleep, preferentially during REMS. No wake-to-REMS transitions occur in humans without narcolepsy. 5 Research article Bioscience Horizons • Volume 7 2014 Figure 4. The AAS. Plus signs denote wake-promoting neurons and minus signs denote sleep-promoting neurons. The AAS consists of a thalamic (green) and extrathalamic (red) pathway. The wake–sleep switch and REMS–NREMS switch involve activity in mainly components of the extrathalamic pathway. See Table 1 for abbreviations. Adapted with permission from Saper, Scammell and Lu (2005). contains regions essential for non- vegetative levels of arousal: cholinergic projections from the parabrachial nucleus (PB) and pre-locus coeruleus region (P-LC) (Fuller et al., 2011). Moreover, photostimulation of the BF evokes immediate tran- sitions from only NREMS to either wakefulness or REMS (Han et al., 2014). Therefore, the extrathalamic route appears to be more involved with arousal state transitions than the thalamic route (Fig. 4). All arousal state transitions require activity from multiple AAS regions, as rodents with lesions of any single AAS region still experience wakefulness, NREMS and REMS (Fuller et al., 2011). In this manner, LHA neurons may synchronize the discharge of multiple AAS neuronal pop- ulations to increase the likelihood of arousal state transitions at times which are favourable to the homeostatic and circa- Figure 5. Functional models of the AAS: flip-flop switch models of dian processes of sleep. transitions between arousal states. (A) The wake–sleep switch: The flip- Orexin and MCH neurons as inputs of AAS flop switch (orange) involves reciprocal inhibition between wake- promoting and sleep-promoting neurons; orexin increases wake- flip-flop switches promoting activity. Monoaminergic wake-promoting regions have been omitted for clarity. (B) The REMS–NREMS switch: the flip-flop Functional models of AAS circuitry have been used to explain switch (orange) involves reciprocal inhibition between REMS-off (vlPAG) arousal state transitions in mammals. The wake–sleep switch and REMS-on (P-LC and SLD) neurons. MCH neurons prolong REMS describes transitions between wakefulness and sleep (NREMS) episode duration by inhibiting vlPAG REMS-off neurons. See Table 1 for (Saper, Chou and Scammell, 2001), and the REMS–NREMS abbreviations. Adapted with permission from Saper et al. (2010). switch describes transitions between NREMS and REMS dur- ing sleep (Lu et al., 2006). These models consist of mutually nuclei (vlPO and mnPO) and wake-promoting cholinergic inhibitory connections, as seen in an electrical flip-flop circuit, (LDT and PPT) and glutamatergic (P-LC and PB) brainstem which enable dichotomous transitions between arousal states. nuclei, with additional wake-promoting input from monoami- The wake–sleep switch (Fig. 5A) consists primarily of recip- nergic nuclei (dRN, LC, TMN and vPAG). The wake–sleep rocal GABAergic inhibition between sleep-promoting preoptic switch may incorporate homeostatic sleep pressure in the form 6 Bioscience Horizons • Volume 7 2014 Research article of vlPO activity. Upon waking, wake-promoting regions sleepiness and recurrent wake-to-REMS transitions which directly inhibit the vlPO (Chou et al., 2002) and are activated rarely occur in normal individuals. Narcolepsy is due to a concurrently by orexin neurons (Estabrooke et al., 2001). deficiency of orexin signalling, usually because of a loss of During sustained wakefulness, homeostatic sleep pressure may orexin neurons during late adolescence by an unknown (pos- rise in the form of excitatory input from the mnPO to the vlPO sibly autoimmune) mechanism. The majority of narcoleptic (Gvilia et al., 2006; Suntsova et al., 2007; Saper et al., 2010; cases involve cataplexy, a symptom which involves a tran- Hsieh et al., 2011), until the collective activity of sleep-promot- sient loss of muscle tone and consciousness following strong ing preoptic regions supersede those of wake-promoting regions emotional responses. As cataplexy can be triggered by envi- to evoke a wake-to-NREMS transition. The wake–sleep switch ronmental cues and there is presently no evidence indicating may also incorporate circadian processes in the form of projec- that narcoleptic bouts have a circadian rhythm, this suggests tions from the SCN to both orexin neurons (Abrahamson, Leak that orexin mediates the homeostatic control of sleep. and Moore, 2001) and preoptic area neurons (Deurveilher and What evidence suggests that narcolepsy is a behavioural Semba, 2005). Orexin neurons may form an input and output manifestation of orexin deficiency? First, orexin deficiency of the SCN, as SCN ablation induces fluctuations in orexin produces narcoleptic phenotypes in many organisms. For cerebrospinal fluid (CSF) levels ( Zhang et al., 2004) and OX example, there is a significant loss of orexin neurons in the inhibits SCN neurons in vitro (Belle et al., 2014). Thus, orexin brains of human narcoleptic patients (Peyron et al., 2000; neurons may promote wakefulness by interacting with both Thannickal et al., 2000; Thannickal, Neinhuis and Siegel, homeostatic and circadian processes of sleep. 2009). Narcolepsy may occur due to a loss of orexin peptide The REMS–NREMS switch (Fig. 5B) consists primarily of signalling, as loss-of-function mutations of OX R DNA reciprocal GABAergic inhibition between REMS-off neurons account for natural and experimental phenotypes of canine −/− in the vlPAG and REMS-on neurons in both the P-LC and the narcolepsy (Lin et al., 1999). Similarly, prepro-orexin and −/− sublaterodorsal nucleus (SLD) (Lu et al., 2006). Here, SLD OX R mice have narcoleptic phenotypes (Chemelli et al., neurons disinhibit P-LC neurons to promote REMS- 1999; Willie et al., 2003). Furthermore, the overexpression associated EEG (Fig. 5B). Moreover, SLD neurons also disin- of prepro-orexin induces an insomnia-like phenotype in hibit medullary interneurons to promote REMS-associated zebrafish ( Prober et al., 2006), whereas the ablation of zebraf- motor atonia. Arousal state transitions within sleep are cur- ish orexin neurons induces a narcolepsy-like phenotype rently attributed to MCH neurons, which can inhibit vlPAG (Elbaz et al., 2012). Second, an orexin CSF level lower REMS-off neurons to initiate NREMS-to-REMS transitions (≤110 pg/mL) than normal (<200 pg/mL) is a cardinal symp- (Saper et al., 2010; Jego et al., 2013). tom for human narcolepsy (Nishino et al., 2000), and orexin CSF concentrations correlate with the number of intact The LHA has three distinct populations of principal neu- orexin neurons in rodents (Gerashchenko et al., 2003). Third, rons: orexin neurons, MCH neurons and neurons containing the onset of narcolepsy is correlated with a decrease in orexin isoform 65 of glutamic acid decarboxylase (GAD ) named CSF levels and weight gain, which suggests that the loss of ‘GAD neurons’ (Karnani et al., 2013). Orexin neurons fire orexin neurons leads to arousal and feeding disturbances in only during wakefulness (Lee et al., 2005), whereas GAD narcolepsy (Savvidou et al., 2013). In summary, narcolepsy and MCH neurons fire only during sleep and fire maximally demonstrates the requirement for orexin neurons to maintain during REMS (Hassani, Lee and Jones, 2009; Hassani et al., wakefulness in mammals, including humans (van den Pol, 2010). These firing profiles may be enforced by tonic activity 2000). from wake-promoting and sleep-promoting AAS regions, as histamine can inhibit MCH neurons potently in vitro (Parks Orexin neurons have been studied in vivo via the photo- et al., 2014). These firing profiles of LHA neurons enable a stimulation of channelrhodopsin-2 (ChR2) in transgenic simplification of the flip-flop switches. Wake-to-NREMS rodent orexin neurons which co-express ChR2 (Ox/ChR2). transitions result from a flip in dominant activity from wake- The photostimulation of Ox/ChR2 neurons can activate fast promoting orexin neurons (wakefulness need) to sleep- AMPA receptor-mediated transmission at 40% of TMN neu- promoting mnPO/vlPO neurons (sleep need) (Fig. 5A). rons, which may govern the temporal precision of the wake– NREMS-to-REMS transitions result from a flip in dominant sleep switch (Schöne et al., 2012). Orexin neurons can induce activity from REMS-off vlPAG neurons to REMS-on P-LC/SLD awakening as the photostimulation of Ox/ChR2 neurons neurons and MCH neurons (Fig. 5B). Thus, orexin neurons during the circadian inactive period (day) significantly prolong the duration of wakefulness and MCH neurons pro- decreases the latency between sleep onset and NREMS-to- long the duration of REMS within the flip-flop models of wake or REMS-to-wake transitions relative to controls AAS circuitry. (Adamantidis et al., 2007), so long as rats are not sleep deprived for longer than 2 h (Carter et al., 2009). Moreover, no NREMS or REMS rebound occurs in sleep fragmented by Evidence for the role of orexin in sleep Ox/ChR2 neuron photostimulation (Rolls et al., 2011). This regulation favours the interpretation that orexin neurons ‘lower the Narcolepsy is a sleep disorder affecting ~1 in 2000 people arousal threshold’—the level of wake-promoting activity worldwide and is characterized by excessive daytime required for transitions from sleep to wakefulness—which 7 Research article Bioscience Horizons • Volume 7 2014 may be overridden by homeostatic sleep pressure (Adamantidis, Carter and de Lecea, 2010). This applies at least to orexin neuron projections to the LC, as the photoin- hibition of LC neurons can prevent sleep-to-wake transitions evoked by the photostimulation of Ox/ChR2 neurons (Carter et al., 2012). In summary, optogenetic studies have confirmed the wake-promoting activity of orexin neurons. Evidence for the role of MCH in sleep regulation As MCH neurons fire predominantly during REMS ( Hassani, Lee and Jones, 2009), they may be involved in prolonging REMS duration. This is supported by the hyperactive pheno- −/− type of MCHR mice (Shimada et al., 1998), which exhibit a significant decrease in total REMS duration and REMS epi - sode duration during fasting relative to controls (Willie et al., 2008). Moreover, the duration of REMS episodes is increased by MCH intracerebrovascular (ICV) injections, in a dose- dependent manner (Verret et al., 2003). In particular, MCH neurons appear to mediate homeostatic REMS rebound, as there is an increased c-Fos expression in MCH neurons in rats undergoing total (Modirrousta et al., 2005) or REMS- specific ( Hanriot et al., 2007; Kitka et al., 2011) sleep depri- vation relative to controls. Figure 6. T he feeding circuit. Optogenetic experiments have identified six projections which can each evoke food foraging when Two photostimulation studies have supported the ability active. Orexin neurons may disinhibit food foraging via excitatory of MCH neurons to promote REMS in vivo. Firstly, MCH input to GABAergic AgRP-PVH projections. It is not known whether neuron photostimulation at the onset of an REMS episode MCH neurons interact directly with ARC neurons. POMC neurons prolongs its duration (≈  45%), whereas MCH neuron photo- promote taste aversion via inhibition of AgRP neurons. GAD neurons stimulation at the onset of an NREMS episode increases the require investigation. See Table 1 for abbreviations. likelihood (≈  80%) of NREMS-to-REMS transitions (Jego et al., 2013). Further investigation showed that REMS epi- (POMC) neurons and rat insulin promoter-cre (RIP-Cre) sode duration can be increased by the photostimulation of neurons. MCH terminals in the TMN and medial septum, which indi- cates that MCH neurons inhibit certain wake-promoting The photostimulation of AgRP neurons evokes foraging monoaminergic regions during REMS. Secondly, MCH neu- and voracious feeding behaviour in rats, which indicates that ron photostimulation during the circadian active period these neurons may determine hunger (Aponte, Atasoy and (night) significantly decreases the duration of wakefulness Sternson, 2011). To date, six axon projections are known to and increases the frequency of all transitions between arousal evoke feeding when photostimulated (Fig. 6B), four of which states other than REMS-to-NREMS transitions (Konadhode are inhibitory AgRP neuronal projections to other feeding et al., 2013). In summary, optogenetic studies have indicated circuit regions (Betley et al., 2013). The largest subpopula- that MCH neuron signalling can potently increase the dura- tion of AgRP neurons projects to oxytocinergic neurons of tion and frequency of REMS episodes. the paraventricular hypothalamus (PVH). As food intake quantities evoked by AgRP neuron photostimulation are sim- ilar to those evoked by the chemogenetic silencing of PVH Feeding behaviour neurons, the connectivity between AgRP and PVH neurons The feeding circuit may be particularly important for feeding (Atasoy et al., 2012). This is supported by the additional presence of projec- Feeding regulation involves ARC neuron responses to input tions from the PVH to the AgRP, which evoke feeding when signals such as leptin, as congenital leptin resistance is corre- chemogenetically and optogenetically stimulated (Krashes lated with human obesity (Montague et al., 1997), and leptin et al., 2014). The photostimulation of AgRP neuronal projec- can depolarize ARC neurons ex vivo (Cowley et al., 2001). tions to the LHA can also evoke feeding; however, the LHA Foraging, taste aversion and caloric intake involve a neuronal neuronal populations involved remain unidentified ( Betley circuit here described as the feeding circuit (Fig. 6A–C), et al., 2013). which includes connections to and from the three GAB- Aergic neuronal populations of the ARC: agouti-related pep- Adult rats undergo fatal starvation following AgRP neu- tide/neuropeptide Y (AgRP) neurons, proopiomel anocortin ron ablation (Luquet et al., 2005), which signifies the 8 Bioscience Horizons • Volume 7 2014 Research article requirement of AgRP neurons for feeding. Fatal starvation indicate that rising blood glucose levels may reduce feeding due to AgRP neuron ablation requires PB activity, as the via the hyperpolarization of excitatory (orexin neurons) and pharmacological inhibition of PB neurons following AgRP depolarization of inhibitory (MCH neurons) input to AgRP neuron ablation enables a full recovery of food intake and neurons. However, it is currently unknown whether MCH body weight (Wu, Boyle and Palmiter, 2009; Wu, Clark and neurons project to the ARC. Third, AgRP and POMC neu- Palmiter, 2012). The ablation of AgRP neurons may disin- rons project to both orexin and MCH neurons (Elias et al., hibit PB neurons, as AgRP neurons inhibit oxytocinergic 1999), and there is in vitro evidence that AgRP neurons PVH neurons during food deprivation (Atasoy et al., 2012), inhibit MCH neurons (Hintermann et al., 2001; van den Pol and oxytocinergic PVH neurons mediate leptin-induced et al., 2004). In summary, the interconnectivity between LHA weight loss via projections to the PB (Perello and Raingo, and ARC neurons indicates that LHA neurons may be sig- 2013). Therefore, AgRP input to the PVH may be critical to nificant inputs to the feeding circuit (Fig. 5A). the regulation of body weight (Fig. 6B–C). The ablation of AgRP neurons may also disinhibit POMC neurons—the sec- Orexin neurons motivate palatable ond neuropeptidergic population of ARC neurons—as AgRP consumption neuron photostimulation elicits a strong GABAergic inhibi- tion of POMC neurons (Atasoy et al., 2012). The photostim- Orexin neurons may not significantly regulate normal feed - −/− ulation of POMC neurons can decrease food intake and body ing, as prepro-orexin and wild-type mice consume similar weight (Aponte, Atasoy and Sternson, 2011), which indicates quantities of chow (Sharf et al., 2010). However, the photo- that like the PB, POMC neurons mediate taste aversion, per- stimulation of neuronal terminals from the bed nucleus of the haps in response to excessive food quantities or toxins (Jensen stria terminalis (aBNST) to glutamatergic LHA neurons can et al., 1990; Halatchev and Cone, 2005; Niikura et al., 2013). evoke the consumption of highly palatable food (HPF) in well-fed mice (Fig. 6B) (Jennings et al., 2013). This indicates The photostimulation of RIP-Cre neurons can increase that orexin neurons mediate the excessive consumption of energy expenditure (oxygen intake and weight loss) without HPF. Excessive HPF consumption relies on orexin peptide altering food intake significantly ( Kong et al., 2012). This signalling, as a selective OX R antagonist or a dual OX R/ 1 1 increase in energy expenditure involves a change in brown adi- OX R antagonist, but not a selective OX R antagonist, can 2 2 pose tissue (BAT) activity mediated by RIP-Cre neurons, which reduce HPF intake significantly without altering chow intake monosynaptically innervate PVH neurons projecting to the (Piccoli et al., 2012). This is further supported by numerous nucleus of the solitary tract (NTS) (Fig. 6C). As the raphe pal- studies wherein OX R antagonists reduce the self- lidus (RPa) regulates BAT activity (Morrison and Nakamura, administration of sucrose (Akiyama et al., 2004; Choi et al., 2011), RIP-Cre neurons may coordinate autonomic responses 2010; Jupp et al., 2011; Cason and Aston-Jones, 2013). associated with feeding via NTS input to RPa. These findings indicate that selective OX R antagonists are potential pharmacological candidates for treating compulsive eating disorder, although the neuronal populations or recep- Orexin and MCH neurons as inputs tor mechanisms by which OX R activation mediates exces- of the feeding circuit sive HPF consumption remain to be investigated. Contrary to the RIP-Cre neuronal pathway, which may Orexin may also modulate arousal in response to HPF con- adjust energy expenditure relative to food intake (Fig. 6C), sumption. The replacement of regular chow with HPF LHA connectivity with the ARC may adjust food intake rela- increases the frequency of cataplexic events in narcoleptic tive to energy demands (Fig. 5A). First, orexin neurons proj- −/− prepro-orexin mice (Clark et al., 2009; Oishi et al., 2013). ect directly to the ARC (de Lecea et al., 1998; Date et al., The genetic ablation of orexin neurons in fasting mice causes 1998), where many AgRP and POMC neurons co-express the a decrease in wakefulness during the circadian inactive period leptin receptor and OX R (Funahashi et al., 2003). Orexin (day) relative to fasting wild-type controls (Yamanaka et al., neurons can depolarize AgRP neurons (van den Top et al., 2003). This suggests a functional overlap between LHA cir- 2004; Wu et al., 2013) and POMC neurons (Guan et al., cuits which regulate hunger and sleep. Orexin may maintain 2001; Burdakov, Liss and Ashcroft, 2003; Acuna-Goycolea arousal in animals starving during circadian inactive periods and van den Pol, 2009), whereas leptin can decrease the firing to prioritize starvation as a greater survival threat than sleep rate of both ARC (Rauch et al., 2000) and orexin neurons (Jo deprivation or an attack from predators (Sakurai, 2007). et al., 2005). Moreover, the overexpression of orexin peptide Orexin may prevent fatal starvation also during hypersomnia, provides resistance to hyperglycaemia and obesity due to a as low glucose levels after prolonged sleep could disinhibit leptin-dependent increase in energy expenditure (Funato wake-promoting orexin activity to reinstate foraging. et al., 2009). Thus, the opposition between (orexigenic) orexin and (anorexigenic) leptin signalling to ARC neurons MCH neurons motivate caloric consumption may regulate food intake relative to energy demands. Second, orexin neurons can be hyperpolarized in vitro via glucose Equivalent doses of MCH and OX ICV injections evoke simi- (Burdakov et al., 2005, 2006) and MCH neurons can be lar increases in food intake (Edwards et al., 1999). However, depolarized in vitro via glucose (Kong et al., 2010), which unlike orexin and NPY mRNA, rat MCH mRNA expression 9 Research article Bioscience Horizons • Volume 7 2014 does not rise during the consumption of a non-caloric sweetener such as saccharin (Furudono et al., 2005). Moreover, MCH may not reinforce non-caloric feeding, as the systemic administration of an MCHR1 antagonist (GW803430) can reduce glucose- reinforced, but not saccharin-reinforced, lever pressing (Karlsson et al., 2012). This indicates that MCH neurons respond to the caloric density, but not the palatability, of ingested food. Recent developments in mammalian taste perception sug- gest that MCH neurons regulate a taste-independent preference for caloric feeding. Sweet taste requires receptor signalling by long transient receptor potential channel 5 (TRPM5), as many sweet caloric and non-caloric compounds fail to induce action potentials in major nerves innervating the taste receptors of −/− trpm5 mice (Zhang et al., 2003). However, the sweet-blind −/− phenotype of trpm5 mice maintains a preference for ingesting (caloric) sucrose over (non-caloric) sucralose which is corre- lated with a post-ingestion release of dopamine in the ventral tegmental area (de Araujo et al., 2008). A recent optogenetic study has identified that this caloric-specific preference and −/− dopaminergic activity is absent in trpm5 mice lacking MCH neurons (Domingos et al., 2013). These results indicate that MCH neurons are essential to the taste-independent reinforce- ment of caloric intake. In summary, during low blood glucose levels, orexin neurons motivate HPF consumption, whereas MCH neurons motivate ongoing caloric consumption. Concluding remarks Future directions Figure 7. Evidence for distinct roles of orexin and MCH in sleep and feeding regulation. Neuronal stimulation: optogenetic of c-Fos Although the experimental manipulation of orexin and MCH analysis. Neuropeptide stimulation: neuropeptide administration or neurons can influence arousal and feeding behaviour (Fig. 7), up-regulation. Neuronal inhibition: optogenetic, lesion or c-Fos many details remain unaddressed. Although there is evidence analysis. Neuropeptide inhibition: knockout of neuropeptide or specific neuropeptide receptors. for a direct activity of orexin (Zhu et al., 2003; Yamanaka et al., 2010; Aracri et al., 2013) and MCH (Gao and van den Pol, 2001) in synaptic transmission, it is unknown whether orexin neurons. Finally, these methods could study how exter- synchronous neurotransmitter release is required for neuro- nal stimuli may influence arousal, as rodent LC ( Hickey et al., peptide release. A direct quantification of neuropeptide con - 2014) and dRN (Ito et al., 2013) photostimulation appears to tributions to postsynaptic currents would also be helpful to elevate arousal during nociception. determine whether they are independently capable of depo- With regard to feeding, ChR2-assisted or chemogenetic- larizing postsynaptic neurons. Additionally, the postsynaptic assisted circuit mapping of the interconnectivity between targets of GAD neurons and RIP-Cre neurons remain to be LHA and ARC neurons is required to directly support LHA characterized. neurons as inputs to ARC neurons (Fig. 6). The ablation or With regard to sleep, the further use of optogenetic and che- temporary inactivation of the six axonal projections known mogenetic approaches could enable a more detailed investiga- to evoke feeding in rodents would clarify which, if any, are tion of arousal state transitions. For example, vlPO required for feeding (Fig. 6B). The anterograde tracing of photostimulation could directly support the wake–sleep switch AgRP neurons may identify which projections to the PB are model (Fig. 5A), and vlPAG photostimulation could directly required for survival. Finally, it is unknown whether the pho- −/− support the REMS–NREMS switch model (Fig. 5B). The pho- tostimulation of orexin neurons in trpm5 sweet-blind mice tostimulation of SCN inputs to orexin and MCH neurons would be sufficient to induce a preference for HPF diets. could also help determine to what extent the wake–sleep switch and REMS–NREMS switch is influenced by circadian Orexin and MCH neurons regulate arousal processes (Abrahamson, Leak and Moore, 2001). Furthermore, with respect to hunger these methods could test new hypotheses of sleep regulation, A healthy animal avoids sleep deprivation and hunger by such as whether narcoleptic wake–REMS transitions result sleeping soon after eating and eating soon after awakening. from the disinhibition of MCH neurons following the loss of 10 Bioscience Horizons • Volume 7 2014 Research article Aracri, P., Banfi, D., Pasini, M. E. et al. (2013) Hypocretin (orexin) regulates This behavioural strategy may be regulated by orexin and glutamate input to fast-spiking interneurons in layer V of the Fr2 MCH neurons, as these neurons have prominent roles in the region of the murine prefrontal cortex, Cerebral Cortex. http://www. neuronal circuits which regulate sleep and feeding. Within ncbi.nlm.nih.gov/pubmed/24297328 (02 October 2014). the AAS, orexin neurons prolong wakefulness duration (Fig. 5A), whereas MCH neurons prolong REMS duration Atasoy, D., Betley, J. N., Su, H. H. et al. 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(2003) Hypothalamic and  -insensitive G-proteins, Journal of Pharmacological Sciences, orexin neurons regulate arousal according to energy balance in 92 (3), 259–266. mice, Neuron, 38 (5), 701–713. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding regulation

O'Leary, Liam Anuj
Bioscience Horizons , Volume 7 – Oct 15, 2014
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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu008 Review Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding regulation Liam Anuj O’Leary Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK *Corresponding author: Email: zcbthj2@ucl.ac.uk Project Supervisor: Dr Jason Rihel, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Tel: +44 020 3549 5508. Email: j.rihel@ucl.ac.uk Orexin and melanin-concentrating hormone (MCH) neurons reside in the lateral hypothalamic area (LHA) and regulate sleep and feeding behaviour in mammals. In rodents, orexin neurons are implicated in the regulation of wakefulness or palatable con- sumption, whereas MCH neurons are implicated in the regulation of rapid eye movement sleep episode duration or caloric con- sumption. This review explores the molecular, genetic and neuronal components of orexin and MCH signalling as mediators of arousal state transitions. These peptidergic signalling systems, which interconnect both with sleep centres in the LHA and feed- ing centres in the arcuate nucleus, may maintain the balance between sleep need and duration with hunger and food foraging. Key words: orexin, melanin-concentrating hormone, lateral hypothalamic area, arcuate nucleus, sleep, feeding Submitted on 8 April 2014; accepted on 8 September 2014 Introduction neuropeptides released from LHA principal neurons, which can cause narcolepsy in many mammalian species (Lin et al., Hypothalamic regulation of sleep 1999). Feeding regulation also involves a neuronal circuit, and feeding here described as the feeding circuit, which includes input and output regions of the arcuate nucleus (ARC). The importance Sleep and feeding are goal-directed activities which mammals of ARC neurons for feeding behaviour is demonstrated by the must perform to survive. Sleep deprivation and hunger are ablation of ARC principal neurons, which can cause fatal especially suitable for studying in animal models, as sleep and starvation in adult rats (Luquet et al., 2005). Both the AAS feeding are not evidently reliant on volition, emotion or intel- and the feeding circuit are modulated by the neuropeptide- ligence (Le Doux, 2012; Sternson, 2013). While the require- mediated activity of principal neurons in the LHA, namely ment of feeding for survival is self-evident, there is also ample orexin (also known as hypocretin) and melanin-concentrating evidence from sleep deprivation studies which indicates that hormone (MCH) neurons (see Table 1 for abbreviations). sleep is also required for mammalian survival (Rechtschaffen This review proposes that orexin and MCH neurons form sig- et al., 1983; Campbell and Tobler, 1984; Bentivoglio and nificant inputs to the AAS and the feeding circuit to enable Grassi-Zucconi, 1997). Sleep regulation involves a neuronal crosstalk between sleep and feeding regulation. circuit known as the ascending arousal system (AAS), which includes projections to the neocortex from the brainstem and Orexin: structure and signalling mechanisms subcortical nuclei such as the lateral hypothalamic area (LHA). The importance of LHA neurons for arousal There are two mammalian peptide isoforms of orexin, maintenance is demonstrated by the genetic knockout of orexin-A (OX ) and orexin-B (OX ), which are each encoded A B © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons 1 1 Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Research article Bioscience Horizons • Volume 7 2014 Table 1. Abbreviations in text and figures Symbol Definition Symbol Definition AAS Ascending arousal system MCHR1 Melanin-concentrating hormone receptor 1 ACh Acetylcholine MCHR2 Melanin-concentrating hormone receptor 1 AgRP Agouti-related peptide mEPSCs Miniature excitatory postsynaptic currents α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic AMPA mnPO Medial preoptic area acid NA Noradrenaline ARC Arcuate nucleus NEI Neuropeptide E-I BF Basal forebrain NGE Neuropeptide G-E ChR2 Channelrhodopsin-2 CSF Cerebrospinal fluid NREMS Non-rapid eye movement sleep DA Dopamine NTS Nucleus of the solitary tract dRN Dorsal raphe nucleus OX Orexin-A EEG Electroencephalography OX Orexin-B EMG Electromyography OX/ChR2 Orexin/Channelrhodopsin-2 EOG Electrooculography PAG Periaqueductal grey EPSP Excitatory postsynaptic potential PB Parabrachial nucleus GABA γ-aminobutyric acid P-LC Pre-locus coeruleus GAD Isoform 65 of glutamic acid decarboxylase Pmch Pro-melanin-concentrating hormone GAD Isoform 67 of glutamic acid decarboxylase POMC Proopiomelanocortin Glu Glutamate PPT Pedunculopontine tegmentum GPCRs G protein-coupled receptors PVH Paraventricular hypothalamus His Histamine PVT Paraventricular thalamus hMCHR1 Human melanin-concentrating hormone receptor 1 REMS Rapid eye movement sleep hMCHR2 Human melanin-concentrating hormone receptor 2 RIP-Cre Rat insulin promoter-cre hOX R Human orexin 1 receptor RPa Raphe pallidus hOX R Human orexin 2 receptor SCN Suprachiasmatic nucleus HPF Highly palatable food ICV Intracerebrovascular SLD Sublaterodorsal tegmentum LC Locus coeruleus SWS Slow-wave sleep; N3 LDT Laterodorsal tegmentum TMN Tuberomammillary nucleus LHA Lateral hypothalamic area TRPM5 Long transient receptor potential channel 5 NPY Neuropeptide Y vlPAG Ventrolateral periaqueductal grey N1 Non-rapid eye movement sleep 1; drowsy sleep vlPO Ventrolateral preoptic area N2 Non-rapid eye movement sleep 2 vPAG Ventral periaqueductal grey N3 Non-rapid eye movement sleep 3; SWS 5-HT 5-Hydroxytryptamine MCH Melanin-concentrating hormone 2 Bioscience Horizons • Volume 7 2014 Research article by one of the two exons of the prepro-orexin gene (Fig. 1 affinity for OX and OX (Sakurai et al., 1998). Orexin can A B A–B) and formed after alternative splicing of the prepro- facilitate excitatory postsynaptic potentials mediated by glu- orexin peptide in mice and humans (Miyoshi et al., 2001). tamate release from orexin neurons (Zhu et al., 2003) and Both OX and OX can bind to orexin receptor 1 (OX R) can depolarize orexin neurons ex vivo (Yamanaka et al., A B 1 and orexin receptor 2 (OX R) in vitro (Fig. 1D–E), which are 2010). Thus, orexin generally potentiates excitatory trans- G protein-coupled receptors (GPCRs) that can couple to mul- mission mediated by orexin neuronal terminals. tiple Gα-subtypes including Gα , Gα , Gα and Gα (Sakurai s i o q et al., 1998; Kim et al., 2004; Karteris et al., 2005). The MCH: structure and signalling mechanisms orexin receptors have different affinity profiles for orexin peptide isoforms (Fig. 1C): OX R is selective by one order of Human MCH is one of three neuropeptides encoded by the magnitude for OX over OX , whereas OX R has equal Pmch gene (Pedeutour, Szpirer and Nahon, 1994) and can A B 2 Figure 1. Orexin signalling. (A) Both orexin-A (OX ) and orexin-B (OX ) are encoded by a single exon of the prepro-orexin gene. (B) Unlike OX , A B B OX has two disulphide bonds (black lines). Almost half (46%, black circles) of OX peptide sequence is conserved with OX peptide sequence. A B A (C) OX and OX act via two GPCRs named OX R and OX R. OX has twice the affinity for OX R than for OX R, whereas OX has equal affinity for A B 1 2 A 1 2 B both OX R and OX R. (D) There are unique (white circles), conserved (black circles) and insertion (grey circles) regions in the peptide sequences 1 2 of human OX R (hOX R) and OX R (hOX R). (E) Potential signalling mechanisms of rat OX R/OX R. Adapted from Tsujino and Sakurai (2013). 1 1 2 2 1 2 3 Research article Bioscience Horizons • Volume 7 2014 bind to two related GPCRs (Hawes et al., 2000; Wang et al., contain mRNA for isoform 67 of glutamic acid decarboxyl- 2001), MCH receptor 1 (MCHR1) and MCH receptor 2 ase (GAD ) (Harthoorn et al., 2005; Elias et al., 2008; (MCHR2) (Fig. 2A–D). Only ‘higher order’ mammals such Rondini et al., 2010; Sapin et al., 2010), and in vitro MCH as ferrets, dogs and primates express functional MCHR2 signalling decreases the frequency of minature excitatory (Tan et al., 2002). Rodent MCHR1 utilizes primarily Gα postsynaptic potentials (mEPSCs) (Gao and van den Pol, i/o signalling but also other unidentified G α signalling path- 2001). Thus, MCH potentiates inhibitory GABAergic trans- ways (Hawes et al., 2000) (Fig. 2E). All MCH neurons mission mediated by MCH neuronal terminals (Fig. 2). Figure 2. MCH signalling. (A) The human prepro-MCH (PMCH) gene encodes neuropeptide G-E (NGE), neuropeptide E-I (NEI) and MCH. (B) NGE and NEI have no effect on MCH signalling; MCH is a non-adecapeptide containing one disulphide bond. ( C) MCH binds with relatively similar binding affinity to both MCHR1 and MCHR2. ( D) There are unique (white dots), conserved (black dots) and insertion (grey dots) sequences in the peptide sequences of human MCHR1 (hMCHR1) and MCHR2 (hMCHR2). (E) Potential signalling mechanisms of rat MCHR1, hMCHR1 and hMCHR2. 4 Bioscience Horizons • Volume 7 2014 Research article maintained by the suprachiasmatic nucleus (SCN), which Sleep regulation can be entrained by cyclic environmental cues including light exposure. Definitions of sleep and the arousal circuit: AAS Vertebrates can transition from one arousal state (wakeful- Sleep is a global state that involves major changes in behav- ness, NREMS or REMS) to another in response to changes in iour, consciousness and cognition. In mammals, sleep is activity within the AAS (Saper, Scammell and Lu, 2005). Most composed of four distinct stages defined by cortical electro - AAS regions are either wake promoting or sleep promoting, encephalography (EEG) activity: rapid-eye movement sleep with the latter class subdivided into those which promote (REMS) and three stages of non-rapid eye movement sleep REMS (REMS-on) and those which promote NREMS (NREMS) named NREMS 1 (N1), NREMS 2 (N2) and (REMS-off). The AAS is divided into thalamic and extratha- NREMS 3 (N3) sleep (Fig. 3). The timing of REMS and lamic routes (Fig. 4): pedunculopontine (PPT) and laterodor- NREMS is regulated by two general processes, homeostatic sal tegmentum (LDT) projections to the thalamus, or midbrain and circadian processes (Borbély, 1982). Homeostatic pro- projections through the reticular formation to the basal fore- cesses govern the rise of sleep pressure during wakefulness brain (BF) (Fuller and Lu, 2009). The extrathalamic system and the dissipation of sleep pressure during sleep. consists of the dorsal raphe nucleus (dRN), locus coeruleus Homeostatic processes also govern sleep rebound, which is a (LC), LHA, tuberomammillary nucleus (TMN), ventral compensatory increase in NREMS or REMS duration (vPAG) and ventrolateral (vlPAG) periaqueductal grey, and following sleep deprivation. Circadian processes govern the ventrolateral (vlPO) and medial (mnPO) preoptic nucleus sleep onset relative to an internal 24 h clock-like rhythm (see Table 1 for abbreviations). The extrathalamic route Figure 3. Sleep: polysomnography, hypnogram, orexin and MCH neuronal recordings in a healthy individual. Wakefulness involves gamma (25–80 Hz) and beta (14–25 Hz) EEG waves; conscious relaxation involves alpha (8–13 Hz) waves. There are four stages of sleep across REMS and NREMS. During NREMS 1 (N1), theta waves (4–7 Hz) predominate, accompanied with a partial loss of consciousness. During NREMS 2 (N2), sleep spindles (series of 11–16 Hz waves which are usually maximal nearest the median wave) and K-complexes (sharp bi- or tri-phasic waveforms) predominate. During NREMS 3 (N3), also known as slow-wave sleep, slow, high amplitude delta (0–4 Hz) waves predominate. During REMS (grey column), also known as paradoxical sleep as (desynchronized) waves resemble wakefulness, distinct sawtooth wave (serrated 2–6 Hz waves), rapid eye movements (EOG) and motor atonia (EMG) recordings appear. Orexin neurons are active only during wakefulness. MCH neurons are active only during sleep, preferentially during REMS. No wake-to-REMS transitions occur in humans without narcolepsy. 5 Research article Bioscience Horizons • Volume 7 2014 Figure 4. The AAS. Plus signs denote wake-promoting neurons and minus signs denote sleep-promoting neurons. The AAS consists of a thalamic (green) and extrathalamic (red) pathway. The wake–sleep switch and REMS–NREMS switch involve activity in mainly components of the extrathalamic pathway. See Table 1 for abbreviations. Adapted with permission from Saper, Scammell and Lu (2005). contains regions essential for non- vegetative levels of arousal: cholinergic projections from the parabrachial nucleus (PB) and pre-locus coeruleus region (P-LC) (Fuller et al., 2011). Moreover, photostimulation of the BF evokes immediate tran- sitions from only NREMS to either wakefulness or REMS (Han et al., 2014). Therefore, the extrathalamic route appears to be more involved with arousal state transitions than the thalamic route (Fig. 4). All arousal state transitions require activity from multiple AAS regions, as rodents with lesions of any single AAS region still experience wakefulness, NREMS and REMS (Fuller et al., 2011). In this manner, LHA neurons may synchronize the discharge of multiple AAS neuronal pop- ulations to increase the likelihood of arousal state transitions at times which are favourable to the homeostatic and circa- Figure 5. Functional models of the AAS: flip-flop switch models of dian processes of sleep. transitions between arousal states. (A) The wake–sleep switch: The flip- Orexin and MCH neurons as inputs of AAS flop switch (orange) involves reciprocal inhibition between wake- promoting and sleep-promoting neurons; orexin increases wake- flip-flop switches promoting activity. Monoaminergic wake-promoting regions have been omitted for clarity. (B) The REMS–NREMS switch: the flip-flop Functional models of AAS circuitry have been used to explain switch (orange) involves reciprocal inhibition between REMS-off (vlPAG) arousal state transitions in mammals. The wake–sleep switch and REMS-on (P-LC and SLD) neurons. MCH neurons prolong REMS describes transitions between wakefulness and sleep (NREMS) episode duration by inhibiting vlPAG REMS-off neurons. See Table 1 for (Saper, Chou and Scammell, 2001), and the REMS–NREMS abbreviations. Adapted with permission from Saper et al. (2010). switch describes transitions between NREMS and REMS dur- ing sleep (Lu et al., 2006). These models consist of mutually nuclei (vlPO and mnPO) and wake-promoting cholinergic inhibitory connections, as seen in an electrical flip-flop circuit, (LDT and PPT) and glutamatergic (P-LC and PB) brainstem which enable dichotomous transitions between arousal states. nuclei, with additional wake-promoting input from monoami- The wake–sleep switch (Fig. 5A) consists primarily of recip- nergic nuclei (dRN, LC, TMN and vPAG). The wake–sleep rocal GABAergic inhibition between sleep-promoting preoptic switch may incorporate homeostatic sleep pressure in the form 6 Bioscience Horizons • Volume 7 2014 Research article of vlPO activity. Upon waking, wake-promoting regions sleepiness and recurrent wake-to-REMS transitions which directly inhibit the vlPO (Chou et al., 2002) and are activated rarely occur in normal individuals. Narcolepsy is due to a concurrently by orexin neurons (Estabrooke et al., 2001). deficiency of orexin signalling, usually because of a loss of During sustained wakefulness, homeostatic sleep pressure may orexin neurons during late adolescence by an unknown (pos- rise in the form of excitatory input from the mnPO to the vlPO sibly autoimmune) mechanism. The majority of narcoleptic (Gvilia et al., 2006; Suntsova et al., 2007; Saper et al., 2010; cases involve cataplexy, a symptom which involves a tran- Hsieh et al., 2011), until the collective activity of sleep-promot- sient loss of muscle tone and consciousness following strong ing preoptic regions supersede those of wake-promoting regions emotional responses. As cataplexy can be triggered by envi- to evoke a wake-to-NREMS transition. The wake–sleep switch ronmental cues and there is presently no evidence indicating may also incorporate circadian processes in the form of projec- that narcoleptic bouts have a circadian rhythm, this suggests tions from the SCN to both orexin neurons (Abrahamson, Leak that orexin mediates the homeostatic control of sleep. and Moore, 2001) and preoptic area neurons (Deurveilher and What evidence suggests that narcolepsy is a behavioural Semba, 2005). Orexin neurons may form an input and output manifestation of orexin deficiency? First, orexin deficiency of the SCN, as SCN ablation induces fluctuations in orexin produces narcoleptic phenotypes in many organisms. For cerebrospinal fluid (CSF) levels ( Zhang et al., 2004) and OX example, there is a significant loss of orexin neurons in the inhibits SCN neurons in vitro (Belle et al., 2014). Thus, orexin brains of human narcoleptic patients (Peyron et al., 2000; neurons may promote wakefulness by interacting with both Thannickal et al., 2000; Thannickal, Neinhuis and Siegel, homeostatic and circadian processes of sleep. 2009). Narcolepsy may occur due to a loss of orexin peptide The REMS–NREMS switch (Fig. 5B) consists primarily of signalling, as loss-of-function mutations of OX R DNA reciprocal GABAergic inhibition between REMS-off neurons account for natural and experimental phenotypes of canine −/− in the vlPAG and REMS-on neurons in both the P-LC and the narcolepsy (Lin et al., 1999). Similarly, prepro-orexin and −/− sublaterodorsal nucleus (SLD) (Lu et al., 2006). Here, SLD OX R mice have narcoleptic phenotypes (Chemelli et al., neurons disinhibit P-LC neurons to promote REMS- 1999; Willie et al., 2003). Furthermore, the overexpression associated EEG (Fig. 5B). Moreover, SLD neurons also disin- of prepro-orexin induces an insomnia-like phenotype in hibit medullary interneurons to promote REMS-associated zebrafish ( Prober et al., 2006), whereas the ablation of zebraf- motor atonia. Arousal state transitions within sleep are cur- ish orexin neurons induces a narcolepsy-like phenotype rently attributed to MCH neurons, which can inhibit vlPAG (Elbaz et al., 2012). Second, an orexin CSF level lower REMS-off neurons to initiate NREMS-to-REMS transitions (≤110 pg/mL) than normal (<200 pg/mL) is a cardinal symp- (Saper et al., 2010; Jego et al., 2013). tom for human narcolepsy (Nishino et al., 2000), and orexin CSF concentrations correlate with the number of intact The LHA has three distinct populations of principal neu- orexin neurons in rodents (Gerashchenko et al., 2003). Third, rons: orexin neurons, MCH neurons and neurons containing the onset of narcolepsy is correlated with a decrease in orexin isoform 65 of glutamic acid decarboxylase (GAD ) named CSF levels and weight gain, which suggests that the loss of ‘GAD neurons’ (Karnani et al., 2013). Orexin neurons fire orexin neurons leads to arousal and feeding disturbances in only during wakefulness (Lee et al., 2005), whereas GAD narcolepsy (Savvidou et al., 2013). In summary, narcolepsy and MCH neurons fire only during sleep and fire maximally demonstrates the requirement for orexin neurons to maintain during REMS (Hassani, Lee and Jones, 2009; Hassani et al., wakefulness in mammals, including humans (van den Pol, 2010). These firing profiles may be enforced by tonic activity 2000). from wake-promoting and sleep-promoting AAS regions, as histamine can inhibit MCH neurons potently in vitro (Parks Orexin neurons have been studied in vivo via the photo- et al., 2014). These firing profiles of LHA neurons enable a stimulation of channelrhodopsin-2 (ChR2) in transgenic simplification of the flip-flop switches. Wake-to-NREMS rodent orexin neurons which co-express ChR2 (Ox/ChR2). transitions result from a flip in dominant activity from wake- The photostimulation of Ox/ChR2 neurons can activate fast promoting orexin neurons (wakefulness need) to sleep- AMPA receptor-mediated transmission at 40% of TMN neu- promoting mnPO/vlPO neurons (sleep need) (Fig. 5A). rons, which may govern the temporal precision of the wake– NREMS-to-REMS transitions result from a flip in dominant sleep switch (Schöne et al., 2012). Orexin neurons can induce activity from REMS-off vlPAG neurons to REMS-on P-LC/SLD awakening as the photostimulation of Ox/ChR2 neurons neurons and MCH neurons (Fig. 5B). Thus, orexin neurons during the circadian inactive period (day) significantly prolong the duration of wakefulness and MCH neurons pro- decreases the latency between sleep onset and NREMS-to- long the duration of REMS within the flip-flop models of wake or REMS-to-wake transitions relative to controls AAS circuitry. (Adamantidis et al., 2007), so long as rats are not sleep deprived for longer than 2 h (Carter et al., 2009). Moreover, no NREMS or REMS rebound occurs in sleep fragmented by Evidence for the role of orexin in sleep Ox/ChR2 neuron photostimulation (Rolls et al., 2011). This regulation favours the interpretation that orexin neurons ‘lower the Narcolepsy is a sleep disorder affecting ~1 in 2000 people arousal threshold’—the level of wake-promoting activity worldwide and is characterized by excessive daytime required for transitions from sleep to wakefulness—which 7 Research article Bioscience Horizons • Volume 7 2014 may be overridden by homeostatic sleep pressure (Adamantidis, Carter and de Lecea, 2010). This applies at least to orexin neuron projections to the LC, as the photoin- hibition of LC neurons can prevent sleep-to-wake transitions evoked by the photostimulation of Ox/ChR2 neurons (Carter et al., 2012). In summary, optogenetic studies have confirmed the wake-promoting activity of orexin neurons. Evidence for the role of MCH in sleep regulation As MCH neurons fire predominantly during REMS ( Hassani, Lee and Jones, 2009), they may be involved in prolonging REMS duration. This is supported by the hyperactive pheno- −/− type of MCHR mice (Shimada et al., 1998), which exhibit a significant decrease in total REMS duration and REMS epi - sode duration during fasting relative to controls (Willie et al., 2008). Moreover, the duration of REMS episodes is increased by MCH intracerebrovascular (ICV) injections, in a dose- dependent manner (Verret et al., 2003). In particular, MCH neurons appear to mediate homeostatic REMS rebound, as there is an increased c-Fos expression in MCH neurons in rats undergoing total (Modirrousta et al., 2005) or REMS- specific ( Hanriot et al., 2007; Kitka et al., 2011) sleep depri- vation relative to controls. Figure 6. T he feeding circuit. Optogenetic experiments have identified six projections which can each evoke food foraging when Two photostimulation studies have supported the ability active. Orexin neurons may disinhibit food foraging via excitatory of MCH neurons to promote REMS in vivo. Firstly, MCH input to GABAergic AgRP-PVH projections. It is not known whether neuron photostimulation at the onset of an REMS episode MCH neurons interact directly with ARC neurons. POMC neurons prolongs its duration (≈  45%), whereas MCH neuron photo- promote taste aversion via inhibition of AgRP neurons. GAD neurons stimulation at the onset of an NREMS episode increases the require investigation. See Table 1 for abbreviations. likelihood (≈  80%) of NREMS-to-REMS transitions (Jego et al., 2013). Further investigation showed that REMS epi- (POMC) neurons and rat insulin promoter-cre (RIP-Cre) sode duration can be increased by the photostimulation of neurons. MCH terminals in the TMN and medial septum, which indi- cates that MCH neurons inhibit certain wake-promoting The photostimulation of AgRP neurons evokes foraging monoaminergic regions during REMS. Secondly, MCH neu- and voracious feeding behaviour in rats, which indicates that ron photostimulation during the circadian active period these neurons may determine hunger (Aponte, Atasoy and (night) significantly decreases the duration of wakefulness Sternson, 2011). To date, six axon projections are known to and increases the frequency of all transitions between arousal evoke feeding when photostimulated (Fig. 6B), four of which states other than REMS-to-NREMS transitions (Konadhode are inhibitory AgRP neuronal projections to other feeding et al., 2013). In summary, optogenetic studies have indicated circuit regions (Betley et al., 2013). The largest subpopula- that MCH neuron signalling can potently increase the dura- tion of AgRP neurons projects to oxytocinergic neurons of tion and frequency of REMS episodes. the paraventricular hypothalamus (PVH). As food intake quantities evoked by AgRP neuron photostimulation are sim- ilar to those evoked by the chemogenetic silencing of PVH Feeding behaviour neurons, the connectivity between AgRP and PVH neurons The feeding circuit may be particularly important for feeding (Atasoy et al., 2012). This is supported by the additional presence of projec- Feeding regulation involves ARC neuron responses to input tions from the PVH to the AgRP, which evoke feeding when signals such as leptin, as congenital leptin resistance is corre- chemogenetically and optogenetically stimulated (Krashes lated with human obesity (Montague et al., 1997), and leptin et al., 2014). The photostimulation of AgRP neuronal projec- can depolarize ARC neurons ex vivo (Cowley et al., 2001). tions to the LHA can also evoke feeding; however, the LHA Foraging, taste aversion and caloric intake involve a neuronal neuronal populations involved remain unidentified ( Betley circuit here described as the feeding circuit (Fig. 6A–C), et al., 2013). which includes connections to and from the three GAB- Aergic neuronal populations of the ARC: agouti-related pep- Adult rats undergo fatal starvation following AgRP neu- tide/neuropeptide Y (AgRP) neurons, proopiomel anocortin ron ablation (Luquet et al., 2005), which signifies the 8 Bioscience Horizons • Volume 7 2014 Research article requirement of AgRP neurons for feeding. Fatal starvation indicate that rising blood glucose levels may reduce feeding due to AgRP neuron ablation requires PB activity, as the via the hyperpolarization of excitatory (orexin neurons) and pharmacological inhibition of PB neurons following AgRP depolarization of inhibitory (MCH neurons) input to AgRP neuron ablation enables a full recovery of food intake and neurons. However, it is currently unknown whether MCH body weight (Wu, Boyle and Palmiter, 2009; Wu, Clark and neurons project to the ARC. Third, AgRP and POMC neu- Palmiter, 2012). The ablation of AgRP neurons may disin- rons project to both orexin and MCH neurons (Elias et al., hibit PB neurons, as AgRP neurons inhibit oxytocinergic 1999), and there is in vitro evidence that AgRP neurons PVH neurons during food deprivation (Atasoy et al., 2012), inhibit MCH neurons (Hintermann et al., 2001; van den Pol and oxytocinergic PVH neurons mediate leptin-induced et al., 2004). In summary, the interconnectivity between LHA weight loss via projections to the PB (Perello and Raingo, and ARC neurons indicates that LHA neurons may be sig- 2013). Therefore, AgRP input to the PVH may be critical to nificant inputs to the feeding circuit (Fig. 5A). the regulation of body weight (Fig. 6B–C). The ablation of AgRP neurons may also disinhibit POMC neurons—the sec- Orexin neurons motivate palatable ond neuropeptidergic population of ARC neurons—as AgRP consumption neuron photostimulation elicits a strong GABAergic inhibi- tion of POMC neurons (Atasoy et al., 2012). The photostim- Orexin neurons may not significantly regulate normal feed - −/− ulation of POMC neurons can decrease food intake and body ing, as prepro-orexin and wild-type mice consume similar weight (Aponte, Atasoy and Sternson, 2011), which indicates quantities of chow (Sharf et al., 2010). However, the photo- that like the PB, POMC neurons mediate taste aversion, per- stimulation of neuronal terminals from the bed nucleus of the haps in response to excessive food quantities or toxins (Jensen stria terminalis (aBNST) to glutamatergic LHA neurons can et al., 1990; Halatchev and Cone, 2005; Niikura et al., 2013). evoke the consumption of highly palatable food (HPF) in well-fed mice (Fig. 6B) (Jennings et al., 2013). This indicates The photostimulation of RIP-Cre neurons can increase that orexin neurons mediate the excessive consumption of energy expenditure (oxygen intake and weight loss) without HPF. Excessive HPF consumption relies on orexin peptide altering food intake significantly ( Kong et al., 2012). This signalling, as a selective OX R antagonist or a dual OX R/ 1 1 increase in energy expenditure involves a change in brown adi- OX R antagonist, but not a selective OX R antagonist, can 2 2 pose tissue (BAT) activity mediated by RIP-Cre neurons, which reduce HPF intake significantly without altering chow intake monosynaptically innervate PVH neurons projecting to the (Piccoli et al., 2012). This is further supported by numerous nucleus of the solitary tract (NTS) (Fig. 6C). As the raphe pal- studies wherein OX R antagonists reduce the self- lidus (RPa) regulates BAT activity (Morrison and Nakamura, administration of sucrose (Akiyama et al., 2004; Choi et al., 2011), RIP-Cre neurons may coordinate autonomic responses 2010; Jupp et al., 2011; Cason and Aston-Jones, 2013). associated with feeding via NTS input to RPa. These findings indicate that selective OX R antagonists are potential pharmacological candidates for treating compulsive eating disorder, although the neuronal populations or recep- Orexin and MCH neurons as inputs tor mechanisms by which OX R activation mediates exces- of the feeding circuit sive HPF consumption remain to be investigated. Contrary to the RIP-Cre neuronal pathway, which may Orexin may also modulate arousal in response to HPF con- adjust energy expenditure relative to food intake (Fig. 6C), sumption. The replacement of regular chow with HPF LHA connectivity with the ARC may adjust food intake rela- increases the frequency of cataplexic events in narcoleptic tive to energy demands (Fig. 5A). First, orexin neurons proj- −/− prepro-orexin mice (Clark et al., 2009; Oishi et al., 2013). ect directly to the ARC (de Lecea et al., 1998; Date et al., The genetic ablation of orexin neurons in fasting mice causes 1998), where many AgRP and POMC neurons co-express the a decrease in wakefulness during the circadian inactive period leptin receptor and OX R (Funahashi et al., 2003). Orexin (day) relative to fasting wild-type controls (Yamanaka et al., neurons can depolarize AgRP neurons (van den Top et al., 2003). This suggests a functional overlap between LHA cir- 2004; Wu et al., 2013) and POMC neurons (Guan et al., cuits which regulate hunger and sleep. Orexin may maintain 2001; Burdakov, Liss and Ashcroft, 2003; Acuna-Goycolea arousal in animals starving during circadian inactive periods and van den Pol, 2009), whereas leptin can decrease the firing to prioritize starvation as a greater survival threat than sleep rate of both ARC (Rauch et al., 2000) and orexin neurons (Jo deprivation or an attack from predators (Sakurai, 2007). et al., 2005). Moreover, the overexpression of orexin peptide Orexin may prevent fatal starvation also during hypersomnia, provides resistance to hyperglycaemia and obesity due to a as low glucose levels after prolonged sleep could disinhibit leptin-dependent increase in energy expenditure (Funato wake-promoting orexin activity to reinstate foraging. et al., 2009). Thus, the opposition between (orexigenic) orexin and (anorexigenic) leptin signalling to ARC neurons MCH neurons motivate caloric consumption may regulate food intake relative to energy demands. Second, orexin neurons can be hyperpolarized in vitro via glucose Equivalent doses of MCH and OX ICV injections evoke simi- (Burdakov et al., 2005, 2006) and MCH neurons can be lar increases in food intake (Edwards et al., 1999). However, depolarized in vitro via glucose (Kong et al., 2010), which unlike orexin and NPY mRNA, rat MCH mRNA expression 9 Research article Bioscience Horizons • Volume 7 2014 does not rise during the consumption of a non-caloric sweetener such as saccharin (Furudono et al., 2005). Moreover, MCH may not reinforce non-caloric feeding, as the systemic administration of an MCHR1 antagonist (GW803430) can reduce glucose- reinforced, but not saccharin-reinforced, lever pressing (Karlsson et al., 2012). This indicates that MCH neurons respond to the caloric density, but not the palatability, of ingested food. Recent developments in mammalian taste perception sug- gest that MCH neurons regulate a taste-independent preference for caloric feeding. Sweet taste requires receptor signalling by long transient receptor potential channel 5 (TRPM5), as many sweet caloric and non-caloric compounds fail to induce action potentials in major nerves innervating the taste receptors of −/− trpm5 mice (Zhang et al., 2003). However, the sweet-blind −/− phenotype of trpm5 mice maintains a preference for ingesting (caloric) sucrose over (non-caloric) sucralose which is corre- lated with a post-ingestion release of dopamine in the ventral tegmental area (de Araujo et al., 2008). A recent optogenetic study has identified that this caloric-specific preference and −/− dopaminergic activity is absent in trpm5 mice lacking MCH neurons (Domingos et al., 2013). These results indicate that MCH neurons are essential to the taste-independent reinforce- ment of caloric intake. In summary, during low blood glucose levels, orexin neurons motivate HPF consumption, whereas MCH neurons motivate ongoing caloric consumption. Concluding remarks Future directions Figure 7. Evidence for distinct roles of orexin and MCH in sleep and feeding regulation. Neuronal stimulation: optogenetic of c-Fos Although the experimental manipulation of orexin and MCH analysis. Neuropeptide stimulation: neuropeptide administration or neurons can influence arousal and feeding behaviour (Fig. 7), up-regulation. Neuronal inhibition: optogenetic, lesion or c-Fos many details remain unaddressed. Although there is evidence analysis. Neuropeptide inhibition: knockout of neuropeptide or specific neuropeptide receptors. for a direct activity of orexin (Zhu et al., 2003; Yamanaka et al., 2010; Aracri et al., 2013) and MCH (Gao and van den Pol, 2001) in synaptic transmission, it is unknown whether orexin neurons. Finally, these methods could study how exter- synchronous neurotransmitter release is required for neuro- nal stimuli may influence arousal, as rodent LC ( Hickey et al., peptide release. A direct quantification of neuropeptide con - 2014) and dRN (Ito et al., 2013) photostimulation appears to tributions to postsynaptic currents would also be helpful to elevate arousal during nociception. determine whether they are independently capable of depo- With regard to feeding, ChR2-assisted or chemogenetic- larizing postsynaptic neurons. Additionally, the postsynaptic assisted circuit mapping of the interconnectivity between targets of GAD neurons and RIP-Cre neurons remain to be LHA and ARC neurons is required to directly support LHA characterized. neurons as inputs to ARC neurons (Fig. 6). The ablation or With regard to sleep, the further use of optogenetic and che- temporary inactivation of the six axonal projections known mogenetic approaches could enable a more detailed investiga- to evoke feeding in rodents would clarify which, if any, are tion of arousal state transitions. For example, vlPO required for feeding (Fig. 6B). The anterograde tracing of photostimulation could directly support the wake–sleep switch AgRP neurons may identify which projections to the PB are model (Fig. 5A), and vlPAG photostimulation could directly required for survival. Finally, it is unknown whether the pho- −/− support the REMS–NREMS switch model (Fig. 5B). The pho- tostimulation of orexin neurons in trpm5 sweet-blind mice tostimulation of SCN inputs to orexin and MCH neurons would be sufficient to induce a preference for HPF diets. could also help determine to what extent the wake–sleep switch and REMS–NREMS switch is influenced by circadian Orexin and MCH neurons regulate arousal processes (Abrahamson, Leak and Moore, 2001). Furthermore, with respect to hunger these methods could test new hypotheses of sleep regulation, A healthy animal avoids sleep deprivation and hunger by such as whether narcoleptic wake–REMS transitions result sleeping soon after eating and eating soon after awakening. from the disinhibition of MCH neurons following the loss of 10 Bioscience Horizons • Volume 7 2014 Research article Aracri, P., Banfi, D., Pasini, M. E. et al. (2013) Hypocretin (orexin) regulates This behavioural strategy may be regulated by orexin and glutamate input to fast-spiking interneurons in layer V of the Fr2 MCH neurons, as these neurons have prominent roles in the region of the murine prefrontal cortex, Cerebral Cortex. http://www. neuronal circuits which regulate sleep and feeding. Within ncbi.nlm.nih.gov/pubmed/24297328 (02 October 2014). the AAS, orexin neurons prolong wakefulness duration (Fig. 5A), whereas MCH neurons prolong REMS duration Atasoy, D., Betley, J. N., Su, H. H. et al. 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Journal

Bioscience Horizons – Oxford University Press

Published: Oct 15, 2014

Keywords: orexin melanin-concentrating hormone lateral hypothalamic area arcuate nucleus sleep feeding

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