종 설 J Kor Sleep Soc / Volume 2 / June, 2005 울산대학교의과대학서울아산병원신경과학교실 Motor Control during Sleep SunJuChung,M.D. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine The regulation of motor system during awake-sleep states is controlled by well-organized system. During wakefulness, most somatic muscles exhibit a background level of activity. During nonrapid eye movement (NREM) sleep, there is a slight decrease in somatic muscle activity compared with that during wakefulness. During REM sleep, there is a dramatic reduction in ongoing muscle activity to theextent that even background muscle tone is abolished. Throughout REM sleep, there is tonic inhibition of motoneurons, as well as phasically occurring brief periods of motoneuron excitation. There are various sleep disorders that involve abnormal patterns of motor inhibition, excitation, or both. These disorders occur in part, or in whole, because of the abnormal expression of the mechanisms that control muscle activity during REM sleep. Key Words : Motor control, Rapid eye movement, Nonrapid eye movement 인간은각성상태에서수면에들면서근육섬유의수축의정도, 즉근긴장(muscle tone) 이감소한다. 1,2 수면중근긴장의저하는 1947년 Pakhomov가 hydrodynamic system of tubes 를이용하여손가락굴근의근긴장의감소를처음으로보고하였다. 3 수면주기중렘수면 (rapid eye movement sleep, REM sleep) 동안에는근긴장이완전히사라지는무긴장(atonia) 이발생한다. 1 인간을포함한여러동물에서비렘수면 (nonrapid eye movement sleep, NREM sleep) 동안은근긴장이감소하고, 렘수면동안은무긴장이나타난다. * Address of correspondence Sun Ju Chung, M.D. Depertment of Neurology, Asan Medical Center, University of Ulsan College of Medicine 388-1 Pungnap-2dong, Songpa-gu, Seoul, Korea Tel: +82-2-3010-3988 Fax: +82-2-474-4691 E-mail: sjchung@amc.seoul.kr 근긴장을결정하는중요한인자는운동신경원 (motoneuron) 을조절하는신경회로와신경전달물질이다. 따라서, 본문에서는수면과각성상태동안운동신경원을흥분시키거나억제시키는고유인자에대해논하였다. 또한, 운동신경원을흥분시키거나억제시키는뇌간의해부학적구조와기전에대해설명하였다. I. 수면과각성중운동신경원의흥분성 1. 수면중운동신경원정지막전위(resting membrane potential) 의조절 운동신경원의흥분성을나타내주는지표중하나가막전위의분극(polarization) 정도이다. 운동신경원이서서히과분극(hyperplarization) 화될때는흥분도가비교적감 Vol.2, No.1 / June, 2005 11
소하게되고, 탈분극(depolarization) 화될때는흥분도가증가하게된다. 2. 각성과비렘수면사이의전환 고양이를이용한동물실험에서, 휴식을취하고있는각성상태에서비렘수면으로전환되면운동신경원의막전위는약간증가하거나변화를보이지않는다. 4 반면, 고양이가활발하게활동을하던중비렘수면에진입하게되면막전위가증가되어과분극을일으킨다. 비렘수면에서각성상태로의전환때는막전위의탈분극이동반된다 (Figure 1). 탈분극의정도는각성의정도와비교적일치한다. 3. 비렘수면에서렘수면으로의전환 비렘수면에비해렘수면에서의운동신경원은과분극을나타낸다 (Figure 2). 운동신경원의과분극은 electroencephalographic desynchronization과근전도에서보이는근긴장의감소와일치를보이고, 근전도에서보이는근긴장의억제기간보다더긴시간동안과분극상태를유지한다. 4. 렘수면에서각성으로의전환 운동신경원의막전위는각성이시작되면서빠르게탈분극을일으킨다 (Figure 2). 또한, 수면이시작되는비렘수면이전의처음각성상태에비해더과도하게탈분극을보인다. II. 렘수면동안운동신경원에대한억제조절 운동신경원의고유기능은시냅스(synapse) 를통해나타난다. 따라서, 시냅스에서의신경전달을시냅스후전압 (postsynaptic potential) 을통해알아보고자한다. 1. 수면과각성중자발성억제성시냅스후전압의비교 비렘수면과각성의경우운동신경원의세포내기록에서억제성시냅스후전압 (inhibitory postsynaptic potentials, IPSPs) 이나흥분성시냅스후전압(excitatory postsynaptic potentials, EPSPs) 은매우드물게관찰된다. 반면, 렘수면중에는자발성억제성시냅스후전압의숫자가아주많이증가한다 (Figure 3). 특히, 큰진폭의렘수면-특이억제성시냅스후전압(active sleep-specific IPSPs) 은렘수면의아주특징적인소견이다. 따라서, 렘수면동안선택적으로방전(discharge) 하는억제성중간신경원(interneuron) 이존재할것이고, 이들은뇌간에존재하면서척수의운동신경원으로긴축삭(axon) 을투사한다고보고되고있다. 5 렘수면동안위상성기간(phasic periods) 에는시냅스후억제의위상성항진(phasic enhancements) 가나타난다. 또한, 렘수면동안ponto-geniculo-occipital(PGO)waves 가나타나면, 운동신경원은억제성시냅스후전압을보인다. Figure 1. Intracellular recording from a trigeminal jaw-closer motoneuron: chage in membrane potential during quiet sleep compared with wakefulness. When an extended period of quiet sleep was followed by sustained wakefulness, membrane depolarization occurred. The degree of depolarization was positively correlated with the level of arousal and muscular activity, as portrayed in the middle of the figure when a brief increase in neck electromyogram (EMG) activity was correlated with a time-locked decreased in membrane polarization. Membrane potential band pass on polygraphic record: DC to 0.1 Hz. EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram. 12 수면
Figure 2. Intracellular recording from a trigeminal jaw-closer motoneuron: correlation of membrane potential and state changes. The membrane potential increased rather abruptly at 3.5 min in conjuction with the decrease in neck muscle tone and transition from quiet to active sleep. At 12.5 min the membrane depolarized and the animal awakened. After the animal passed into quiet sleep again, a brief, aborted episode of active sleep occurred at 25.5 min that was accompanied by a phasic period of hyperpolarization. A minute later the animal once again entered active sleep, and the membrane potential increased. PGO, ponto-geniculo-occipital potential. Figure 4. A, Distribution of the amplitudes of spontaneous inhibitory postsynaptic potentials (IPSPs) recorded during active sleep from the same lumber motoneuron before (open histogram) and after the microiontophoretic ejection of strychnine (dotted histogram). Arrows indicate the median value of each IPSP population. Note that before strychnine, 50% of the potentials were larger in amplitude than the largest potential that was detected following the microiontophoretic ejection of strychinine (10mM 250nA, 2.75min). B, Averaged ponto-geniculo-occipital (PGO)waves and the membrane potential in lumbar motoneurons recorded in two different cats before (control) (A) and following strychinine injection (B).The vertical bars are positioned at the foot of the averaged PGO waves. After the injection of strychinine, the PGO-related IPSP was no longer present;instead, a long depolarizing potential occurred. Vol.2, No.1 / June, 2005 13
2. 렘수면중운동신경원에대한억제성시냅스조절 에연관된신경전달물질 렘수면동안은자발성억제성시냅스후전압을담당하는신경전달물질은 glycine 이다. 6 Glycine의길항제인 strychnine 을microiontophoretic juxtacellular application을하면렘수면-특이 IPSPs의진폭이작아지거나사라진다 (Figure 4). 반면, gamma-aminobutyric acid(gaba) 의길항제인 picrotoxin이나 bicuculline을같은방법으로실험하면렘수면-특이 IPSPs 에변화가발생하지않는다. 7 또한, strychnine 을microiontophoretic juxtacellular application 을하면렘수면중PGO waves 와연관된억제성시냅스후 전압이 glycinergic synapses 인것을알수있다(Figure 4). III. 렘수면동안운동신경원에대한흥분성조절 렘수면중억제성시냅스후전압은단순히존재하기보다는항진되어나타난다. 렘수면중사지나눈에 twitches 또는 jerks이발생한다는사실은렘수면중운동신경원에대한억제만증가하는것이아니라상당히강력한흥분성자극도존재하는것을시사한다. 8 렘수면중의흥분성자극은운동신경원으로간간히전달되는데, 이는운동신경원이렘수면동안탈분극과극전압을나타내는것으로알수있다 (Figure 5). Figure 5. A, Summated depolarizing potentials and spike activity in conjunction with active sleep periods of rapid eye movements (REMs). During the first burst of eye movements, phasic hyperpolarizing events arose (B). In conjunction with the second burst of eye movements, there was a series of rhythmic depolarizing shifts (C). Action potentials occurred during the third episode of eye movements; they were also present during the interval between the second and third bursts of ocular activity. The recordings over the bars in A are presented at a faster sweep speed and greater magnification in B, C, and D. In D, note that spikes arise from the first and third depolarizing shifts, whereas the second does not reach threshold. The action potentials in C and D are trunchated because of the high gain of the records. Data are unfiltered; records were obtained from a tibial motoneuron(resting membrane potential :-70mV). Figure 6. Distribution of Fo+ neurons in the medulla at the level of the facial nucleus of a control (left) and an AS-carbachol (right) cat. Each dot represents one Fos-labeled neuron. The region that contains double-labeled, Fos+, and cholera toxin + neurons is indicated by the square. 14 수면
IV. 렘수면동안운동신경원에대한뇌간의억제기능 렘수면-특이 IPSPs가존재한다는사실은렘수면동안척수의운동신경원의흥분을조절하는억제성중간신경원 (interneuron) 이존재하는것을시사한다. 이중간신경원은척수상중추(supraspinal center) 의조절을받게된다. 즉, nucleus pontis oralis(npo) 는inhibitory region of Magoun and Rhines(bulbospinal inhibitory zone, BSIZ) 9 을흥분시키고, 다시 BSIZ에서억제성신호가척수의운동신경원으로전달되어렘수면동안근긴장이사라지게된다. 10-12 AS-carbachol 을이용한면역세포화학실험에서렘수면동안medialmedullaryreticularformation 의배측부위에서많은수의 Fos-labeled cells들이관찰되는데(figure 6), 이때Fos-labeled cells이보이는부위가 BSIZ 이다. 9 결과적으로, 렘수면동안의근육의무긴장은콜린성세포로구성된 NPO의신경원들이연수의 BSIZ 를흥분시키고, 다시 BSIZ는척수의운동신경원을억제시킴으로써나타난다고보고되고있다. 13 1. Reticular response-reversal 과운동신경원조절 뇌간의 NPO에같은자극이주어지더라도각성상태에서는운동신경원이활성화되는현상이발생하고, 이와는정반대로렘수면동안은운동신경원이억제되는현상이발생한다. 14,15 즉, 각성중 NPO 에자극이가해지면강력한흥분성시냅스후전압이운동신경원으로전달되고, 똑같은자극이렘수면중 NPO에가해지면억제성시냅스후전압이운동신경원에전달된다. 11,12,16 렘수면동안 NPO의신경원들의활동이증가하고, 이들의신호를받는연수의전운동억제성신경원들의활성이증가하게되어, 결과적으로척수의운동신경원에서 monosynaptic glycinergic postsynaptic inhibition 이발생한다. 각성과렘수면중에는 reticular response-reversal 현상에의해사람이나동물의상태와운동신경원의억제성신호전달과정을조절하는 neuronal switch 가나타난다. 13 각성과렘수면을조절하는신경구조를탐구한한연구에의하면, 억제성신경전달물질인 GABA를 NPO에주입하면각성상태가길게나타나고운동활동성이증가한다. 17 반대로, GABA A 의길항제인 bicuculline을주입하면렘수면 Figure 7. The anatomic location of effective injection sites (n=11) in the rostral pons of six cats (A). Schematic frontal planes of cat brainstem are illustrated at level P 2.5 and P 3.0. Sites where injections were delivered to the left and righe side are indicated by circles and squares, respectively. Representative polygraphic recordings of an episode of spontaneous active sleep (B), an episode of wakefulness which occurred following the injection of bicuculline, a GABA receptor antagonist (D). The injection of GABA was performed during a spontaneous active sleep episode. Note that bicuculline-induced state appears indistinguishable from a spontaneous episode of active sleep;however, the former lasted 52 min, almost eight times longer than the mean time of spontaneous active sleep episodes. BC, Brachium conjunctivum; EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram; LC, locus coeruleus. All vertical bars: 100mV. Vol.2, No.1 / June, 2005 15
이나타나고체운동억제가오랜기간나타난다. 따라서, 각성과렘수면의조절에서교뇌의 GABAergic system 이중요한역할을담당하는것을알수있다 (Figure7). 다른신경조절물질(neuromodulators) 도중요한역할을담당한다. 예로, 고양이의 NPO 에신경성장인자(nerve growth factor, NGF) 를미세주입하면상당시간지속되는렘수면이초래된다 (Figure 8). 18 렘수면에서중요한역할을담당하는 NPO 신경원에 neurotrophinergic input을담당하는신경해부학적구조는 NPO로투사하는 dorsolateral mesopontine tegmentum 의콜린성신경원이다. 이신경원은 neurotrophins을함유하고있으면서 NPO 신경원을자극하여렘수면을유도하는역할을담당한다. 19 따라서, neurotrophins 은 neuromodulator의역할을담당하면서 NPO 신경원을활성화시켜렘수면을발생시키고유지시키는역할을담당한다. V. 기저핵- 뇌간경로 (basal ganglia-brainstem pathway) 기저핵-뇌간경로는자발적운동의자율적인조절뿐아니라 (Figure 9), 각성- 수면상태의조절에도중요한역할을담당한다. 1. 근긴장조절기전 기저핵에서기원한후근긴장의억제기능을담당하는 pedunculopontine tegmental nucleus(ppn) 으로투사되는GABAergic projection 은근긴장조절에서핵심적인역할을담당한다. 대뇌가제거된고양이(decerebrated cat) 를이용한실험에서 midbrain locomotor lesion(mlr) 을전기적으로자극하거나 N-methyl-D-aspartic acid (NMDA) 를미세주입하면근긴장이증가된다 (Figure 10). 20 MLR은 PPN 의배측정중(dorsomedial) 부위에존재하며, 콜린성신경원이거의존재하지않는cuneiformnucleus (CNF) 와비슷한위치이다. 대뇌피질에서시작되는 MLR으로의신호전달은 subthalamic locomotor region(slr) 을통해전달된다. Figure 11 은근긴장억제기전을담당하는해부학적구 Figure 8. Nerve growth factor (NGF) induces rapid eye movement (REM) (active) sleep when injected into the nucleus pontis oralis (NPO) of the cat. Polygraphic recordings illustrating the similarity between a spontaneous REM sleep episode (A) and a REM sleep episode that followed the microinjection of NGF into the NPO (B). The onset of the spontaneous REM sleep episode was preceded by the appearance of ponto-geniculo-occipital (PGO) waves in the lateral geniculate nucleus (LGN) and in 1μl of cehicle) (B). As indicated by the polygraphic recordings, the spontaneous REM sleep episode and the episode that followed NGF microinjection were indistinguishable; however the latter lasted 23 min, almost five times longer than the spontaneous REM sleep episode. Figure 9. Volitional and automatic control of locomotor movements. GABAergic basal ganglia output to the thalamocortical neurons and the brainstem neurons integrate volitional and automatic control processes of movements. 16 수면
Figure 10. Effects of electrical and chemical stimulations of the mesopontine tegmentum. (A) Experimental diagram. Either electrical or chemical stimulation was delivered to the lateral part of the mesopontine tegmentum. (B) Effects on muscle activities following stimulation of the MLR (a) and the PPN (b). Each trace was obtained from the left (L) and right (R) soleus (Sol) muscles. A downward filled arrowhead in (a) indicates the onset of the treadmill. An open triangle in (b) indicates stimulation applied to the left pinna by pinching the scapha. (C) (a) An injection of NMDA into the left MLR increased the bilateral muscle tone. (b) Commencement of the treadmill elicited locomotion. Downward and upward arrows indicate the onset and end of treadmill movements. (c) Two hours after the first injection, NMDA was injected into the left PPN and inhibited the bilateral soleus muscle activity. Pinching the pinna after 5 min (indicated by an open triangle) restored muscle activity. A dashed line above the recording indicates the period of the injection. (D) Effective sites on coronal (a) and parasagittal (b) planes for evoking muscular atonia (filled circles) and locomotion (open circles). (A) Shaded area in both planes indicates the PPN. (E) Distribution of cholinergic neurons stained by choline acetyltransferase (ChAT) immunohistochemistry. Light microscopic photographs of coronal (a and b) and parasagittal (c and d) planes. Lower (a and c) and higher (b and d) magnification are shown in the right and left columns, respectively. Abbreviations: IC, inferior colliculus; CNF, cuneiform nucleus; SCP, superior cerebellar peduncle; PPN, pedunculopontine tegmental nucleus; NRPo, nucleus reticularis pontis oralis; RD, raphe dorsalis. Figure 11. Neural architecture of locomotion executing system (A) and the muscle tone inhibitory system (B). See text for explanation. Abbreviations: ACh, acetycholine; a,a-motoneuron; CPG, central pattern generator; E, extensor motoneurons, F, flexor motoneurons; FRA, flexion reflex afferents; GABA, gaminobutyric acid; LC, locus coeruleus; g,g-motoneuron; PMLS, pontomedullary locomotor strip; PRF, pontine reticular formation; RN, raphe nuclei; RSN, reticulospinal neuron; SLR, subthalamic locomotor region; SNr, substantia nigra pars reticulata; NRGc, the nucleus reticularis gigangocellularis. Vol.2, No.1 / June, 2005 17
조를 설명한 그림이다. PPN을 자극하면 콜린성 pontine 21,22 reticular formation(prf) 신경원을 흥분시킬 수 있고, GABAergic nigrotegmental projection이 어떤 기전에 이 의해 locomotion과 근긴장을 조절하는지에 관한 연구가 있 는 다시 medullary reticulospinal neurons과 척수의 중 었다.20 이 연구는 선조체, 시상, 대뇌피질 등을 제거하고, 간신경원을 흥분시켜, 결과적으로 α-motoneurons을 억제 SNr은 보존한 대뇌가 제거된 고양이(decerebrated cat)를 23 한다. 반대로, monoaminergic systems인 coerulospinal 24 이용한 연구였다(Figure 12). Bicuculline을 MLR에 주입 과 raphespinal tracts 는 근긴장을 일으키는 구조로 알려 하면 움직이는 treadmill에서 locomotion을 일으켰다 지고 있다. PPN으로의 세로토닌 투사가 존재하는데, 이는 (Figure 12B (a)). 반면, bicuculline을 ventrolateral PPN 25 medial 에 주입하면 locomotion을 억제시키면서, 자세유지에 관 PRF로의 세로토닌 투사는 이 억제성 기능의 감소를 유발한 련된 근긴장을 억제시켰다(Figure 12B (b)). 이 실험 결과 mesopontine cholinergic neurons을 억제하고, 26 다. 반대로, 억제성 기전이 coerulospinal tract의 활동 27 는, PPN이나 MLR으로의 GABAergic projection이 각각 근긴장 억제 시스템의 활동을 억제시키고, locomotion을 을 억제한다. Mesopontine tegmentum은 기저핵의 output center인 일으키는 시스템을 억제시킨다는 것을 시사한다. 이와 더 substantia nigra pars reticulate(snr)로부터 억제성 신 불어, SNr의 외측 부위에 conditioning stimuli를 가하면, 28 호를 받는다(nigrotegmental pathway). 이 때 사용되는 PPN에 의해 유발되는 근긴장의 감소가 일어나지 않는다 29 Saitoh 등은 백서(rats) 실 (Figure 12C (b)). 즉, GABAergic nigrotegmental pro- 험에서 SNr을 자극하면 PPN 신경원에서 단일시냅스 jection은 기능적 지정학(functional topography)를 가지 신경전달물질은 GABA이다. 30 IPSPs가 유발된다고 보고했다. 이 때 발생하는 IPSPs는 GABAA 수용체 길항제인 bicuculline에 의해 감소하기 때 고 있는데, SNr의 외측은 근긴장을 담당하고, 내측은 locomotion을 담당한다. 문에, IPSP는 GABAergic projections에 의해 발생한다고 보고되었다. Figure 12. GABAergic nigrotegmental projections control locomotion and muscle tone. (A) Experimental diagram. Either electrical or chemical stimulation was delivered to the SNr, the MLR and the PPN. (B) (a) Quadrupedal locomotion observed at 15 min after injecting bicuculline into the MLR. (b) Another injection of bicuculline into the PPN in the same cat suppressed the locomotion. A dashed line above the recording indicates the period of the injection. Muscle activities were recorded from bilateral triceps brachial (TB) muscles and soleus muscles. (C) Nigral control of postural muscle tone. The effects induced by the SNr (a) and PPN (b) on the postural muscle tone. PPN stimulation (20 ma) completely suppressed muscle tone. (c) When conditioning SNr stimuli of 50 ma were delivered, the PPN-effect was abolished. (D) Nigral control of locomotion. (a) SNr stimulation did not change the level of muscle tone. (b) Locomotion on a moving treadmill belt induced by the MLR. (c) Conditioning SNr stimuli of 30 ma reduced step cycles, delayed the onset (indicated by open arrowhead) and disturbed rhythmic alteration of limb movements of MLR-activated locomotion. 18 수면
2. 렘수면동안의기저핵- 뇌간경로의변화 PPN을포함한 pontomesencephalic reticular formation은ascending reticular activating system(aras) 을구성한다. 31-33 기저핵은두가지기전으로 ARAS를조절하여렘수면에영향을준다. 한가지경로는기저핵에서시상으로의투사이고, 다른한가지는기저핵에서 PPN으로의투사이다. 예로, 대뇌가제거된고양이(decerebrated cat) 를이용한실험에서 PPN의억제지역을자극하면무긴장을동반한렘수면이유도된다(Figure 12C (a)). 또한, SNr의외측부위에 conditioning stimulation을주면 PPN에의해유발된무긴장과렘수면이사라진다 (Figure 12C (b)). 재미있는현상은, SNr의중간부위에 conditioning stimulation 을주면렘수면은사라지는데무긴장은사라지지않는데, 이는렘수면행동질환(REM sleep behavior disorder, RBD) 와비슷한현상이다(Figure 12C (c)). 이런결과는렘수면과근긴장이 SNr을포함한기저핵의영향을받는다는사실을시사한다. VI. 렘수면동안운동신경원의병적상태 인간이나동물에서렘수면을온전하게유지하기위해서는운동억제가필요하다는것은잘알려져있다. 이때 glycine의분비가운동신경원을억제하여무긴장이발생한다는가설도설득력을얻고있다. 따라서, 이과정에문제가발생할경우렘수면중이상운동이발생할수있다. 이에해당되는질환은기면증(narcolepsy)/ 탈력발작(cataplexy), 야간간질발작(nocturnal seizures), 렘수면행동장애 (REM sleep behavior disorder, RBD), 주기적사지운동 (periodic limb movements during sleep), 근간대성연축 (myoclonic twitches) 등이다. VII. 렘수면동안운동억제의이상에의해발생하는병적인운동활성화 렘수면행동장애는병적인렘수면시간동안복잡하고, 강력하며, 때로는격렬한행동이나타난다. 이질환을가진환자에서는근긴장이유지될뿐아니라, 말초근육의강력한수축이동반된다. 주기적사지운동 (periodic limb movements during sleep, PLMS) 은규칙적, 반복적, 상동성의하지근육의수축이발생하는질환이다. 특징적으로엄지발가락이신전하 고, 발목관절이배굴곡(dorsiflexion) 하며, 무릎과둔부의굴곡이규칙적으로발생한다. 하지불안증후군(restless legs syndrome) 은다리의불쾌한감각증상과더불어억제하기힘든다리의움직임을나타내는질환이다. 기면증은탈력발작(carteplexy), 렘수면의장애, 입면렘수면(sleep onset REM periods), 입면환각(hypnagonic hallucination), 수면마비(sleep paralysis) 등의증상을보인다. 기면증환자는렘수면동안운동억제가감소된다고알려지고있다. 치료를받지않은기면증환자에서렘수면동안근긴장이유지된다는것은근전도검사를통해증명되었다. 34 또한, 기면증환자의경우렘수면행동장애도발생하고, 주기적사지운동도정상인에비해많이발생한다. VIII. 렘수면동안병적인운동활성화에서 hypocretin 의역할 Hypocretin (Orexin) 은시상하부에서생성되는단백질로기면증환자에서이상소견을보이는물질이다. 35,36 현재까지 hypocretin이어떤기전과경로에의해수면과각성상태에이상을가져오는지는명확하게밝혀지지않았다. 한가지가능성은 hypocretin이수면과각성을담당하는신경계통, 즉histaminergic neurons in the tuberomammillary nucleus, serotonergic neurons in the dorsal raphe, cholinergic neurons in the laterodorsal tegmental nucleus and the PPN, noradrenergic neurons in the locus ceruleus 등을조절한다는것이다. 35,37-41 고양이를이용한동물실험에서, hypocretinergic axons 은 NPO, nucleus reticularis gigantocellularis, lamina 9 of the lumbar spinal cord 등으로투사되는것으로보고되었다. 42 이부위들은렘수면동안운동억제를담당하는뇌간- 척수시스템과일치한다. 따라서, hypocretinergic system은렘수면동안운동흥분성을조절하는억제시스템을구성하는신경핵과신경회로를조정하는것이다. Hypocretinergic system은시상하부에서시작하여신경계의여러부위로투사되어각성중체운동활성화를일으킨다. 또한, 렘수면중에는앞에서설명한기전에의해운동억제를일으킨다. 즉, hypocretinergic system은각성동안은체운동활동의증가를활성화시키고, 렘수면동안은체운동억제를증가시킨다. 이와같은현상은, 이전에설명한 reticular response-reversal 현상과매우흡사하다. Vol.2, No.1 / June, 2005 19
병적인상태에서 hypocretin 이부족하거나없게되면, 각성동안운동신경원은방전하지못해근육의긴장이감소하거나없어져탈력발작이발생하게된다. 렘수면동안은 hypocretin에의한 NPO를통한운동신경원의억제가되지않아렘수면중이상운동이나타난다. 따라서, hypocretin은 state-dependent manner에의해각성중에는운동신경원을흥분시키고, 렘수면중에는운동신경원을억제시킨다. 수면중에는각성상태와같이여러신경계의조절에의해운동이조절된다. 특히, 기저핵, 뇌간, 척수의신경세포들이신경회로망에의해상호연결이되어있고, 다양한뇌신경물질에의해신경후시냅스의기능적변화가일어나각성- 수면상태에맞게운동상태가조절된다. 최근에는 hypocretin과같은새로운단백질의역할이밝혀지고있어, 에관한연구에많은기여를하고있다. 향후, 수면에관한신경해부학, 신경생리, 신경화학, 신경유전학등의발전은이분야의지식을더욱넓힐것이며, 다양한수면질환에대한새로운치료법의개발이곧현실화될것으로기대한다. REFERENCES 1. Kleitman N. Sleep and Wakefulness. Chicago: The University of Chicago Press, 1963. 2. Pompeiano O. The neurophysiological mechanisms of the postrual and motor events during desynchronized sleep. Res Publ Assoc Res Nerv Ment Dis 1967;45:351-423. 3. Pakhomov A. A new method of measuring and recording muscle tonus, and its application to the study of the physiology of sleep in man. Fiziol Zh SSSR 1947;33:245-254. 4. Chase M. Reticular Formation Revisited. In: Hobson J, Brazier M, eds. The motor functions of the reticular formation are multifaceted and state-determined. New York: Press, 1980: 449. 5. Morales FR, Sampogna S, Yamuy J, Chase MH. c-fos expression in brainstem premotor interneurons during cholinergically induced active sleep in the cat. J Neurosci 1999;19:9508-9518. 6. Young A, McDonald R. Glycine as a spinal neurotransmitter. In: Davidoff R, ed. Handbook of the Spinal Cord. New York: Marcel Dekker, 1983;1. 7. Nistri A. Spinal cord pharmacology of GABA and chemically related amino acids. In: Davidoff R, ed. Handbook of the Spinal Cord. New York: Marcel Dekker, 1983;45. 8. Chase MH, Morales FR. Phasic changes in motoneuron membrane potential during REM periods of active sleep. Neurosci Lett 1982;34:177-182. 9. Magoun H, Rhines R. An inhibitory mechanism in the bulbar reticular formation. J Neurophysiol 1946;9:165-171. 10. Chase MH, Morales FR, Boxer PA, Fung SJ, Soja PJ. Effect of stimulation of the nucleus reticularis gigantocellularis on the membrane potential of cat lumbar motoneurons during sleep and wakefulness. Brain Res 1986;386:237-244. 11. Fung SJ, Boxer PA, Morales FR, Chase MH. Hyperpolarizing membrane responses induced in lumbar motoneurons by stimulation of the nucleus reticularis pontis oralis during active sleep. Brain Res 1982;248:267-273. 12. Yamuy J, Jimenez I, Morales F, Rudomin P, Chase M. Population synaptic potentials evoked in lumbar motoneurons following stimulation of the nucleus reticularis gigantocellularis during carbachol-induced atonia. Brain Res 1994;639:313-319. 13. Chase M, Yamuy J, Xi M, Morales F. The control of motoneurons during sleep. In: Chokroverty S, Hening W, Walters A, eds. Sleep and Movement Disorders. Philadelphia: Butterworth Heinemann, 2003;50-67. 14. Chase M, Morales F. Postsynaptic mechanisms responsible for motor inhibition during active sleep. In: Chase M, Weitzman W, eds. Sleep Disorders: Basic and Clinical Research. New York: Spectrum, 1983;71-94. 15. Chase MH, Babb M. Masseteric reflex response to reticular stimulation reverses during active sleep compared with wakefulness or quiet sleep. Brain Res 1973;59:421-426. 16. Chandler SH, Nakamura Y, Chase MH. Intracellular analysis of synaptic potentials induced in trigeminal jaw-closer motoneurons by pontomesencephalic reticular stimulation during sleep and wakefulness. J Neurophysiol 1980;44:372-382. 17. Xi MC, Morales FR, Chase MH. Evidence that wakefulness and REM sleep are controlled by a GABAergic pontine mechanism. JNeurophysiol1999;82:2015-2019. 18. Yamuy J, Morales FR, Chase MH. Induction of rapid eye movement sleep by the microinjection of nerve growth factor into the pontine reticular formation of the cat. Neuroscience 1995;66:9-13. 19. Yamuy J, Sampogna S, Morales FR, Chase MH. c-fos Expression in mesopontine noradrenergic and cholinergic neurons of the cat during carbachol-induced active sleep: a double-labeling study. Sleep Res Online 1998;1:28-40. 20. Takakusaki K, Habaguchi T, Ohtinata-Sugimoto J, Saitoh K, Sakamoto T. Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction. Neuroscience 2003;119:293-308. 21. Lai YY, Clements JR, Siegel JM. Glutamatergic and cholinergic projections to the pontine inhibitory area identified with horseradish peroxidase retrograde transport and immunohistochemistry. JCompNeurol1993;336:321-330. 22. Mitani A, Ito K, Hallanger AE, Wainer BH, Kataoka K, McCarley RW. Cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei to the pontine gigantocellular tegmental field in the cat. Brain Res 1988;451:397-402. 23. Fung SJ, Barnes CD. Evidence of facilitatory coerulospinal action 20 수면
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