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    Sleep Medicine ESRS

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    eye face eer sd Sleep Research and Sleep Medicine in Europe SLEEP MMIEDICINE TEXTBOOK ee Eke Eo tee are UMP CUR au aa cg European Sleep Research Society ESRS European Sleep Medicine Textbook Editors-in-Chief: Claudio L. Bassetti, Zoran Dogaé, Philippe Peigneux Table of Contents Preface A. Physiological basis of sleep (Soeton Ediors:R. Amiel, 2 Boga’, P Peigneux) t 1. The neurophysiology and novrebilogy of sta PH. Lupp, 2 Adamantiis and P. For 2 Regilaton of sleep an wakehuness 2 Bogat, R, Poootc and Wt. Vale 3. Adapiaion of toa furetlons to soon R.Amic\ and G, Zooech 4. Theories onthe functions a sioep P-Peigneux and R. Leprol 5. flocs uf acute and chronic sloop deprivaon H.-P. Landolt, A. Sousek ana'S.@ Halst 8, Sleep and desiring 1M. Sciveat 7 Ageing and steep: sleep in all stages of human dewolopment Nolin ond R Huber 8. Gender aferenices in step “T Porkka-teskanan, 7. Saaresranta and Polo-Kantla B. Assessment of sleep disorders and diagnostic procedures (Geaton Ediors:T Penzel, M.Zuccon) 1. Classicaton of sop ceorders M.Zucconl and R. Fert 2. The cnet infor and clive oxamination Grate and’ FJ. Putas 3. Measuring - monitoring sleep and wakefunees bir pathways © AdonecneA2e rocptos Figure 2. Nouronal networks responsible for slow-wave (nor-REM) sloop. VLPO and MnPo GABAergic neurons would bo inhibited by ‘noradrenergic and cholinergic inputs during waking. The majority of them would stat ing et steep onset (drowsiness) in response to excitatory, homeostatic (adenosine) and crcadian drives (suprachlasmatc nou). These activated neuron, trough the reciprocal GABAergé inhibition of wake promoting systems, would be In positon to suldenly unbalance the Tip-op’ network, as requied Tor swiching from W (drowsiness) toa consoldation of SWS sleep. Conversoly, the slow remaval of axclatoy influences would result a progressive fring decrease In VLPO. ‘Routons and thoreforo an activation of waks promoting ayetoms leading tothe awakoning overt. GABA, yaminobutyic acd; MnP, modian preoptic nuleus; REM, rapid eye movement; SWS, slow-wave sleep; VLPO, veniroateral preoptic nucleus; W, waking where POA lesions consistenty induced a protound and persistent insomnia (Fort et al, 2008). Consistent with these results, POA oloctrical stimulation induces EEG slow-wave activity and SWS (Fort et al, 2009). Finally, putative sleep- promoting neurons displaying an elevated discharge rate during SWS compared with W, difusely cistbutod within a large region encompassing the horizontal limb of the diagonal, bands of Broca and the lateral POA-substantia innominate, were recorded in trealy-moving cats (Fort ef al, 2009). Attogether, these studies support the hypothesis that the POA encompasses neurone that promote sleep, in particular Ws, This apparent simplicity highly contrasts with the complex network responsible for W, involving redundant neurotrans- milter systems with populations of neurons disseminated from the upper brainstem, caudal hypothalamus to basal forebrain, such as neurons containing acetyicholine, NA, serotonin, histamine and hypocretin (orexin; Fig. 1). It is, thought that during the transition to sleep, the hypnogenic Ccentre(s) would inhibit the multiple arousal systems of the ARAS Via a sustained and coordinated inhibition (Fig. 2) In order to capture a snapshot of the nouronal populations, active during speciic sieep states In the mammalian brain, researchers detected the expression of the immediate-early gene c-Fos, a matker of neuronal activity, using immunohis- tochemistry. These neurons are distributed in the POA, but ‘are mote densely packed in the median preoptic nuclous 1 2014 European Sioop Research Society (MinPn) and the ventrolateral preoptic nucleus (VLPO). Interestingly, the number of c-Fos-immunoreactive neurons in tho VLPO and MnPn positively corrolatod with sloop ‘quantity and sleep consolidation during the last hour preced= ing death. Numerous c-Fos-positive neurons were also ‘observed in sleep-deprived rats in the MnP but not VLPO. (Gulla ot al, 2006; Sherin et al, 1996), suggesting that VLPO nourons are responsible for the induction of sloop hile MoPn neurons serve a homeostatic role in sleep. It was, later demonstrated that VLPO and the suprachiasmatic, rhuclous (SCN), responsible for the circadian organization of the slaep-W cycle, have synchronized activity. Considering that both ateas are interconnected and recelve inpuls from the retinal ganglion cells, itis, thus, possible that clrcadian- ‘and photiclinked information may be conveyed to modulate VLPO activity (Fort et al, 2008; Fig. 2) Electrophysiological experiments In behaving rats have shown that neurons recorded in the VLPO and MnPn are activa before and after the onset of SWS, and thoir firing rato Is posttively correlated with sleep dopth and duration, suggesting that they participate in SWS induction and siabilly, Some of these nourons are also active during PS with a higher fring frequency than during the preceding SWS, In addition, VLPO and MnPn neurons display a fring pattem reciprocal to the wake-active neurons (see below). Retro- grade and anterograde tractiracing studies indicate that VLPO and MnPn neurons are reciprocally connected with 6 PAM. Luppiet al. wake-active neurons, such as those containing histamine in the TMN, hypocretins in the perifornical hypothalamic area, (PeF), serotonin in the DRN, NA in the LC, acetylcholine in tho pontine [laterodorsal tegmental nucleus (LOTYpeduncu- lopontine tegmental nucleus (PPT)] and basal forebrain nuclei. in these wake-promoting areas, extracellular levels, of GABA increase duting SWS compared with W. Ithas also been shown that c-Fos-positive neurons in the VLPO express, galanin mFINA, and 80% of VLPO neurons projecting to the TAN contain both galanin and glutamic acid decarboxylase: (GAD), the GABA-synthesizing enzyme. Finally, electrical stimulation of the VLPO aroa evokes a GABA-modiated inhibition of TMN neurons, suggesting that VLPO and WinPa efferents to the wake-promoting systems are inhibitory (Fort of al, 2009) MECHANISMS CONTROLLING THE ACTIVITY OF THE SWS-INDUCING NEURONS Electrophysiological whole-cell recordings showed that YLPO contains neuronal groups with specific intrinsic mem- brane properties, distinct chemo-morphology and that they are inhibited by most of the W nouratransmiters (Gallopin, ef al, 2000). Sleep-active neurons are GABAergic and galaninergic in nature, mulipolar triangular shaped, and exhibit a potent low-thteshold calcium potential, These neurons are always inhibited by NA, via postsynaptic alpha2-adrenocoptors, Interestingly, NA-inhibited neurons: ‘re also inhibited by acetyicholine, through muscarinic postsynaptic and nicotinic presynaptic actions on NA termi- nals. In contrast, histamine and hypocretin did not modulate the activity of the steep-active neurons (Gallopin ot al, 2000) Finally, serotonin induced either excitation (50%, Type 2) or Inhibition (50%, Type 1) of VLPO neurons (Fort et a, 2008), Homeosiatic regulators, involving natural sleop-promoting ‘actors accumulating during W, play a crucial role in triggering sleep. Among these factors, prostaglandin D2 and adenosine have been functionally implicated in sleep, although thelr neuronal targets and machanisms of action romain largely Unknown. In this context, it has been shown that application fof an adenosine Aza receptor (AoxR) agonist evoked direct excitatory effects specifically in 50% of the sloop-active neurons that are also activated by serotonin (Fort et al, 2009). Adcitional results further suggested that adenosine might directly activate VLPO nourons at sleep onset via an action on postsynaptic ApaR. Indeed, pharmacological infue sion of an Aza agonist into the eubarachnoid space rostral to the VLPO inoreases SWS and induces c-Fos expression in, \VLPO neurons (Lazarus of al, 2011; Fig. 2). However, it has then been demonstrated that inhibition of the exprossion of, ‘Acai? in the shell region of the nucleus accumbans (NAc) Is, sufficient to block the induction of W induced by caffeine (Lazarus et at, 2011), These results suggest that tho induction of sloep by adenosine activation of AzaR results {rom the inhibition of NAc GABAgrgic neurons that disinhibit wake-inducing neurons located in the hypothalamus and the ventral tegmental area, indicating that such a pathway may ‘contribute to sleep induction and maintenance in adeltion to the VLPO (Lazarus et #1, 2011). Besides, a number of studies showed that adonosine Ay receptors (A;R) promote sleep through inhibition ofthe wake- promoting neurons, in particular cholinergic and hypocretia neurons (Porkka-Heiskanen ef al, 2000), However, trans- genic mice that lack A; exhibit normal homeostatic regu: lation of sleep. In contrast, the lack of AzaR prevents normal sleep regulation and blocks the wake-inducing cffect of calfeine, suggesting that the activation of Aza is crucial in SWS (Huang et al, 2005) Overview of the neuronal network responsible for SWS (non-REM) sleep A lerge body of evidence suggests that both the VLPO and tho MnP contain neurons responsible for sleep onset and maintonance (Fig. 2). Although this remains to be domon- strated, the current hypothesis proposed that during wake- fulness, VLPO GABAergic nourone are inhibited by NA and cholinergic inputs while some of them start fing at sleep ‘onset (rowsiness) in response to unidentified excitatory inputs, as well as homeostatic (adenosine and serotonin) and ‘itcadian drives (suprachiasmatic inpud). Conversely, emer- ‘gonce ffom sleep would result from a rapid reactivation of arousal circuits, concomitant with the inhibition of VLPO nourons (Fort et al, 2009) MECHANISMS INVOLVED IN PS (REM) GENESIS ‘The neurons generating PS are localized in the pontine reticular formation twas fist shown that a state charactorized by muscle atonla and REM persists following decortication, cerebellar ablation fr brain stom trangections rostral to th pons and in the: ‘pontine cat’, a preparation in which all the structures rostral to the pons have been removed (Jouvet, 1962; Fig. 3). These results suggested that brainstem siructures aro necessary ‘and sufficient to trigger and maintain the state of PS. Electrolytic and chemical lesions showed that the dorsal part (of pontisoralis (PnO) and caudalis (PAC) nuclei, ao named per:LCa, pontine inhibitory area and subcoeruleus nucleus, contains the neurons responsible for PS onset (Jouvel, 1962). More recently, a corresponding area has been identified in rats, named the sublaterodorsal tegmental ucieus (SLD). It was also shown that a bilateral injestion in cals of a cholinergic agonist, carbachol, ito the PnO and Pn dramatically increases PS quantities in cats (Vann Mercier ef al, 1980). In addition, the PnO and PnC and the adjacent LOT and PPT cholinergic nucle! contain. many rnourons that show a tonic fring selective to PS state (called ‘PS-on' neurons; Sakal and Koyama, 1996). From these early 1970-1980 studies, it was hypothesized that the PS-on neurons generating PS were cholinocoptive and cholinergic. © 2014 European Sleep Research Society Paradoxical (REM) sleep ~~ eonrieat ACTIVATION, a) Wu? Son neurone D wen res ) susonnazons GD) Pentre Pe Bcon pay = Mae ees Inneitorypatways adenosine At receptors CD eset ‘tons Figure 8. Neuronal networks espansibe fr PS (REM), PS onsel would be due othe activation of glutamatergic PS-on naurons localized in the SLD. During W and SWS (non-FEM) sleep, these PS-on neurone would be inhibited by a toni inhibitory GAHAarge: tone originating trom S.off naurens localized in the viPAG and the dDPMo, Those neurons would be activated during W by the Hert neurons and the monoaminergic ‘neurons. The onset of PS would be due to the activation by intinsic mechanisms of PS-on GABAergic neurons localized inthe postotiorlaloral hypothalamic area, the DPGI and the VAG. These nourons would also inactivate the PS-off monoaminersic neurons during PS. The isinhbited ascending SLD PS-on neurons would In tum induce cortical acivation via heir projections to intalaminar thai relay neurons in colaboration with W/FS-on cholinergic and glutamatergic neurons fom he LDT and PPT, mesencephalc ans pontine reticular nucle! and the basal forbrain. Descending PS-on SLD neurons would induce muscle alonia via their excitatory projections to glyinergiepre-moloneurons Ipoalizodin the Gia and GIV. The ext rom PS would be dus fo the activation af waking systems a PS epieadee are almost alway terminated by an arousal. Tho waking ystems would inhibit the GABAergic PS-on neurons localized in the DPGI and vIPAG, Because the duction of PSis negatively coupled with the metaboic rate, canbe proposed thatthe atv ofthe waking systems is tiggeted to end PS to restore competing physiological parameters ike thermoregulation. dDPMe, dorsal part of the deep mesencephalic nucleus; OPGI, dersal paragigantocelular Fetiolar nulous; Gia, alpha glgantoceltarreticuiar nucle; GI, ventral gigantacelar rticular nucll; Hes, hypoctetin, SLD, sublaterodorsal ‘tegmental nuclous; PAG, voniolateral periaquoductal grey PS (REM}-generating neurons: the switch from acetylcholine to glutamate However, in contrast to cats, carbachol iontophoresis into the rat SLD failed to induce a signiicant increase in PS quantities @oissard et al, 2002). Further, only @ few cholinergic neurons were immunostained for c-Fos in the LDT, PPT and SLD after PS hypersomnia (Vertet et af, 2008). Finally, neurochemical lesions in rals of both the LOT and PPT had no effect on PS and cortical activation (Lu et al, 2008). thas been recently further demonstrated that most of the c-Fos positive neurons localized in the SLD after PS recovery express vGlut2 (Clement et al, 2011), suggesting that the PS-on SLD neurons triggoring PS are glutamatergic ‘A number of recent results further suggest that PS-on glutamatergic neurons located in the SLD generate muscle alonia via descending projections to PS-on GABA/glycinergic, pre-motonourons located at the modullary lovel rather than directly in the spinal cord. First, using intracellular recordings: during PS, it has been shown that trigeminal, hypoglossal ‘and spinal motoneurons are tonically hyperpolarized by large inhibitory postsynaptic potentials during PS (Chase et al, 1989}. Furthermore, local iontophoretic pplication of (© 2014 Exropean Sleep Research Society strychnine (a specific antagonist of the inhibitory neurotrans- miltor, glycine} decreased the hyporpolarization of motoncu: rons, suggesting that they are tonicaly inhibiied by slycinergic neurons during PS (Chase ef al, 1980). Interest ingly, it has then been shown that the lovels of glycine and also those of GABA increase within hypoglossal and spinal ‘motor pools during PS-lke alonia, suggesting that GABA, in Addition to glycine, might contribute to the hyperpolarization ff motoneurons during PS (Kodama et al, 2003). Finally, it was recently shown that combined microdialysi¢ of bicucul- line, strychnine and phaciophen (a GABA-B antagonist) inthe trigeminal nucleus is necessary to restore jaw muscle tone during PS (Brooks and Peever, 2072), and that mice with impaired glycinergic and GABAergic transmissions display PS without muscle atonia (Brooks and Peever, 2011). Inaddition, SLD neurons send direct efferent projections to GABAalycinergic neurons located in the nucleus raphe magnus (RMg) and the ventral (GiV), alpha (Gia) giganto: cellular and lateral paragigantocelular (LPG) reticular nuciel (Boissard ef al, 2002). Besides, GABA/alycinergic neurons cf the Gia, GIV, LPGI and Filig express c-Fos aftor induction ‘of PS by bicuculline (a GABA-A antagonist) injection in the SLD (Boissard ef at, 2002). In addition, nearly all 8 P-H, Luppiet al ©-Fos-labolled neurons localized in those nuclei atter 3 of PS recovery following 72 h of PS depsivaion express GADBT_ AIA (Sapin etal, 2008) In view ofall ese results, ican be proposed that the SLD glutamatergic PS-on neurons induce muscle atonia during PS by moans of direct projections to medullary RMg/GiAIGV LPGi. Those neurons hyperpolarize motoneurons mainly using glycine, but also to @ minor extent GABA acting on GABA-A and GABA.B receptors. Ithas also been shown that @ subpopulation of SLD PS-on nourons project to the intralaminar thalamic. nuclei, tho posterior hypothalamus (PH) and the besal forebrain. In dition to the SLD, it has also been shown that cholinergic neurons losated in the PPT and LOT, and glutamatergic neurons located in the re‘cular formation ate active both during W and PS and project rostally to support cortical activation during PS (Boissard et al, 2002; Fort et al, 2009) MECHANISMS RESPONSIBLE FOR THE ACTIVATION OF SLD PS-ON NEURONS DURING, Ps In cals and rats, microdialysis administration in the SLD of, kainic acid, a glutamate agonist, induces a PS-lke state (Boissard of al, 2002). A long-lasting PS-like hypersomnia can also be pharmacologieally induced with a shor latency in, head-restrained unanaesthetized rats by iontophoretic appli: cation into the SLD of bicuculline or gabazine, Iwo GABA-A receplor antagonists (Boissard et al, 2002). Further, appli- cation of kynurenate, a glutamate antagonist, reverses the PS-ke state induced by bicuculine (Boissard et al, 2002). In the head-estrained rat, neurons within the SLD specifically active during PS and oxcited following bicuculine or gab: ‘zine lonlophoresis have beon recorded. Taken together, these data indicate that the activation of SLD PS-on neurons, is mainly duo to the removal during PS of a tonic GABAergic tone present during W and SWS combined with the contin: uous presence of a glutamatorgic input, Combining retro- ‘grade tracing with cholera toxin b subunit (CTB) Injected in, ‘SLD and GAD67 immunohistochemistty or c-Fos immuno: histochemistry with GADS7 mRNA ‘in sity hybridization’ after, 72 h of PS deprivation, it has been recently demonstrated that the ventrolateral part of the periaqueductal grey (vIPAG} ‘and the adjacent dorsal part of the deep mesencephalic hucleus (JDPMe) are the only ponto-medullary structures ‘containing a large number of GABAergic neurons activated during PS deprivation projecting to the SLD (Sapin et a, 2009). Further, injection of a GABA-A agonist (muscimol) into the VIPAG andor the cDPMe induces strong increases in PS. quantiles in cas (Sastre et al, 1996) and rats (Sapin et a, 2008). Finally, neurochemical lesion of these two structures, induces a profound inereases in PS quantities (Lu et al 2006). These congruent experimental data led us to propose that PS-off GABAergic neurons located in the vIPAG and the dDPMe gate PS by inhibiting tonically PS-on neurons of the. SLD during W and SWS. Our results indicate that these GABAergic newons are crucial to gate PS, although they do not rule out a secondary role for monoaminergie neurons a3. inoreases in monoaminergic transmission either by reuptake blockers or agonists is well known to inhibit PS (Luppi ef a, 2011). The targets of monoaminergic neurons responsible {or their inhibitory effects remain to be defined, They can either excite PS-off neurons or inhibit PS-on neurons, One possiblity is that the monoaminergic nourons are exciting the GABAergic PS-off neurons during W 10 preclude PS. onset. Nourons inhibiting the GABAergic and monoaminergic PS-off neurons at the onset and during PS Ithas been previously reported that bicuculline application on serotonergio and NA neurons during SWS or PS resiores 2 tonic tring pattern in both types of neurons (Gervasoni et al, 1996, 2000). These results strongly suggest that an ineroased GABA release is responsible for the PS-selectiva inactivation of monoaminergic neurons. This hypothesis is ‘well supported by microdialysis experiments in cals, which measured a significant increase in GABA release in the DRN and LC during PS as compared with W and SWS, but no. detestablo changes in glycine concentration (Nitz and Siegel, 1997ap), By combining retrograde tracing with CTb and GAD immunohistochemistry in rats, i was found that the VIPAG ‘and the dorsal paragigantocellular nucleus (PGi; Gervasoni ct al, 2000) contained numerous GABAergic neurons pro- Jecting both to the DRN and LC. It was then demonstrated by combining ¢-Fos and retrograde labelling that both nuclei contain numerous LC-projecting neurons selectively acti vated during PS rebound folloning PS deprivation (Verret ‘et al, 2006). Further, it has been found that the DPGi Contains numerous PS-on neurons that increase their activity, speoificaly during PS (Luppi et al, 2011). Taken together, these data strongly suggest that the DPGi contains the neurons responsible for the inactivation of LC NA neurons, during PS (Luppi ef al, 2011). A conisibution from the vIPAG. in the Inhibition during PS of LC NA and dorsal raphe serotonergic neurons Is also likely. Indoed, an increase in c~ FosiGAD-immunoreactive neurons has been reported in the, vIPAG after a PS robound following deprivation in ats (Sapin, ft al, 2008). In summary, a large body of data indicates that GABAergic PS-on neurone localized in the VIPAG and the PGi hyperpotarize the monoaminergic neurons duting PS. has been first proposed thal these neurons might also be responsible for the inhibition of the dOPMoMPAG PS-off GABAergic neurons during PS. To test this hypothesis, neurons active during PS hypersomnia projecting to the DPMoMPAG PS-off GABAergic neurons were recently localized (Clement ef af, 2012). It was found out that the vIPAG and the DPGi, respectively, contained a substantial ‘and a small number of CT/e-Fos double-labelled neurons in, PS hypersomniac rats. Although the GABAergic nature of these neurons romains to be demonstrated, our results, © 2014 European Stoop Research Society Indicate that the vIPAG and the DPGI might contain PS-on GABActgic neurons inhibiting the vIPAGIIDPMe PS-off GABAergic neutons at the onset and during PS, However, it has also been demonstrated that the lateral hypothalamic area (LH) is the only brain siructure containing a very large number of neurons activated during PS hypersomnia and projecting to the vPAG/HOPMe. It has been further dernon- strated that 44% of these neurons oxprass the neuropeptide !melanin-concentrating hormone (MICH). Thase results indl- cate that LH nourons might play a crucial role in PS onset and maintenance by means of descending projections to the vIPAGIdDPIe PS-off GABAorgic neurons. They confirmed, previous data discussed below, indicating that the PH contains neurons implicated in PS control Role of the MCH/GABAergic neurons of the LH in PS. control To localize all the brain areas activated during PS, an extensive mapping of the distibution of ¢-Fos-positive nnoutons in control rats, rats selectively deprived of PS for 72.1 and ras allowed to recover ftom such deprivation has, been done (Verret et al, 2003). Surprisingly, a very large number of ¢-Fos-positive cells was observed in the PH, Including zona inceria (ZI), PeF and LH. These results are in, agreement with the fact that: () bilateral injection of muscimol in the cat mamrmilary and tuberal hypothalamus induces a. drastic inhibition of PS (Lin et al, 1989); and (i) neurons, specifically active during PS were recorded in the PH of cats or head-restrained rats (Goutagny ef al, 2005). By using ing hormone MCH# receptor affects ral sleap-wake architecture Eur J. 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Regulation of sleep and wakefulness ZORAN BOGAS, RENATA PECOTIC and MAJA VALIC Deparment of Neuroscience, Spit Stoop Medilne Conor, School of Medicine, University of Spl, Sokanska 2, Split, 21000, Coala Keywords requlation of sleep, sleep transitons, cora sleep, optional sloop. sleep-promoting neurones, woprocass model, sleep homeastass, Process S, process C, chranotypos and sloop, hormonal regulation of sop, thermoregulation Correspondence Professor Zoran Bogas, Deparmont ot Neuroscionco, Splt Sloop Meciolne Gener, Schoo! of Medizin, Universiyof Spi, Sltansia 2, 24000 Spla, Croatia, Tol: +385 21 597 905; lax: +385 21 587 956; ‘emai: ziogas@mefst hr KEY POINTS + There are two distinct states of sloep defined on the basis of several physiological parameters, rapid eye movement (REM) and non-REM (NREM). Extensive brain neuronal networks are involved in the regulation of wake-sleep and NREM-REM trans tions. + The two-procoss model postulates that sleep is under the contro of citcadian rythm (Process C) and sleep ‘wake homeostasis (Process 8). + The suprachiasmatic nuctous (SCN) is the site of tho master circadian pacemaker that controls circadian, bbehaviourflunctions in mammals. Most cells and tissues of the body also contain and express coro 24h molecular clock mechanisms, ‘Sleep-wake homeostasis donotes a core principle of sleep regulation whereby prolonged periods of wake- fuiness are followed by an increased intensity and uration of sleep, while excessive sleep has the opposite effect. Gonelic studies suggest that the two processes are ‘not compietely independent and that there is a Considerable cross-ialk between them at various levels of organization. Melatonin plays @ role in the regulation of human sleep via its chronobiological effects in terms of induction of sleep as well as atfocting phase-shifting, The human sleep-wake cycle Is coupled to the ‘lrcadian time-course of the core body temperature, © 2014 European Sieep Research Society ‘SUMMARY Wakefulness is characterized by low-amplitude beta waves and alpha rhythm on the human EEG, whereas sleep is characterized by thela waves and spindles, as well as high-amplitude slow delta waves. There are two distinct states of sleep defined on the basis of several physiological parameters, rapid eye movement (REM) and non-REM (NEM). Extensive brain neuronal networks, composed of wakefulness-, NREM- and REM-promoting neurones, are involved in the regulation of wake-sleep and NREM-REM tran- sitions, The wake- and sleep-promoting: neurones appear to be mutually inhibitory. This mutually antag onistic relationship can give rise to behaviour similar to that seen with a ‘flip-flop’ switch. The sleep-wake cycle is regulated by two separate biological mech- anisms, which interact together and balance each ‘other. This mode! is offen relerred to as the ‘two- process model’ of sleep-wake regulation, composed ff Process C, that reflects the ‘circadian rhythm’, and Process S, that reflects the ‘sleep-wake homeosta- sis’. Sleep exerts a modulatory effect on levels of some hormones, whereas the biological timing sys- tem has a more pronounced effect on other hor- mones. Extensive lines of evidence indicate that melatonin plays an important role in the regulation of human sleep. The suprachiasmatic nucleus was identified as a site of chronobioiogical effect of melatonin in terms of affecting phase-shifting, as well as induction of sloep. Sleep regulatory and thermo- regulatory systems are inter-related. The sleep-wake ‘cycle is coupled tightly to the circadian time-course of the core body temperature, but the homeosiatic increase in sleep pressure does not influence the thermoregulatory system, In this chapter, we eumma- ‘ize the homeostatic, citcadian, genetic, hormonal and thermoregulation of the sleep-wake cycle. 18 14 Z Dogas et al DEFINITIONS AND NORMAL SLEEP-WAKE PATTERNS Definitions of sleep-wake states ‘There are many definitons of sloop. According to a simple boehavioural definition, sleep is a reversible behavioural stale Of perceptual disengagement from and relative untespon- siveness to the environment, It is also true that sleep is a Complex amalgam of physiological and behavioural pro- ‘cesses. Sleep is typically (but not necessarily) accompaniad. by postural recumbence, behavioural quiescence, closed eyes and all the other indicators that one associates: commonly with steeping (Carskadon and Dement, 2011). We spend nearly one-thitd of our fives asleep and many mammals, including small laboratory rodents, spend half or more of their existence in this state, Despite the famous line of Kleltman, that "tis pethaps not sleep that needs to be explained, but wakelulness’(Kieitman, 1938), which addressed the Important point that there are different kinds of wakofuiness at different stages of phyloge- netic and ontogenetic development, in this chapter we deal primarily with sleep and its defintions, normal sleep patterns ‘and the basic regulatory mechanisms of sleep-wake states, ‘The presence of sleep could be established conclusively, ‘and continuously and quantitatively measured, without dis: lurbing the sleeper ever since Hans Berger rocorded the electrical activity of the human brain (alactroencephalogram, EEG) and clearly demonstrated differences in these rythms When subjects were awake or asleep. in the human, EEG. wakefulness js characterized by low-amplitude beta waves: and alpha shythm, whereas sleep is characterized by theta waves and spindles, as well as high-amplitude slow dalia waves ‘There are two distinct states of sloep, defined on the basis cf several physiological parameters, Rapid eye movement (REM) and non-REM (NREM) sloep exist in most mammals, studied (See Fig. 1 for a characterization af brain rhythms across sleep-wake states in mice). These states are both different from wakefuiness and cistinct from one another. However, citferentiating sleep (or sleep stages) from quiet wakefulness Is hardly possible at the Sehavioural level. NREM sleep, subdivided formerly into four stages aecorsing to standard Rechtschaffen & Kales (R&K) sleep scoring rules (Rechischaffan and Kales, 1968), is curranty distinguished into three stages according to the American Academy of ‘Sleep Modicine (AASM) scoring rules (Berry et al, 2014: ber ct al, 2007), Those stages aro defined based mainly on the EEG. The EEG pattem in NREM sleep is described commonly @s synchronous, with charactorisic waveforms such as sleep spindles, K-comploxes and high-voltage slow Waves. NREM stages [stages 1, 2, 9 and 4 according lo R&K (Fig. 2a) and stages 1, 2 and 3 according to AASM (Fig. 2b), stage 9 according to ASM being composed of stagas 3 and 4 according to R&x] reprosent a depth-of-sleep continuum, where the arousal threshold is generally lowest in stage 1 and highest in stage 9 (or 4) sleep. Classical studies showed that the sound intensity nooded to awaken a subject is correlated positvely with the depth of slaop, That is, during deep sleep characterized by the siow wave activity, as seen Figure 1. Charactrization of brain rhythms and thei elalive contabuton ascoss slesp-nake slates in mice, (a) Sinusoidal brain waves are

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