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1 종 설 J Kor Sleep Soc / Volume 1 / June, 2006 수면각성조절의신경생물학 조용원 계명대학교신경과 Neurobiology of Sleep-Wake Control Yong-Won Cho, M.D. Department of Neurology, College of Medicine, Keimyung University The regulations of sleep-wake cycle is complicated and many neurochemicals are involved. It is the consequence of an active process requiring appropriate interactions ofbrainstem and the cerebral system. The homeostatic drive and circadian factors are major controls in this regulation. The reticular activation system is a wake promoting area and the neurons in pons and preoptic areas are involved in non-rapid eye movement sleep and rapid eye movement sleep. Sleep is a necessary behavior and it is, at least in part, a restorative process. Good sleep during the nightis important for a healthy condition during the day time. Understanding of these reciprocal sleep-wake interactions should be very important to better understand the effects of many drugs and many other sleep related diseases. Key Words : sleep, arousal, neurobiology 이있다고알려져있다. 2 뇌가수면과각성에관련될것이라는생각은오래전부터있어왔지만수면과각성의신경생물학적기초는 20세기까지잘알려져있지않았다. 1916년빈의신경학자인 BaronConstantinvonEconomo가임상적으로수면과각성의변화를특징적으로나타내는새로운형태의뇌염 -encephalitis lethargica-을보고한것이수면과각성에관한해부학적연구의시초가되었다 (Figure 1). 1 그이후최근까지많은연구들을통해우리의각성상태는모노아민 (monoami nergic) 과콜린(cholinergic) 계의높은활성과관련이있으며, 수면중비램수면은모노아민계와콜린계의낮은활성과관련이있다고알려져있으며램수면은낮은모노아민계활성과높은콜린계의활성이관련 * Address of correspondence Yong-Won Cho, M.D. Department of Neurology, College of Medicine, Keimyung University 194 Dongsan-dong, Jung-gu, Daegu, Korea Tel: Fax: neurocho@dsmc.or.kr I. 각성조절 가. 망상체 (Reticular formation) 망상체는연수부터중뇌까지의신경집합체로써각성에관여하는중요한신경계이며크게두가지경로를통해각성을유지한다. 3 첫번째경로는아세틸콜린을분비하여시상을통해대뇌피질로신경신호를보내각성을유지한다. 그결과진폭이낮고빠른주파수의뇌파소견을나타낸다. 모노아민이관여하는다른경로는시상을거치지않고시상하부를통해대뇌피질로방사되며 waking behavior 와관련된다. 이경로는하이포크레틴( 혹은올렉신) 을포함한외측시상하부와 GABA 혹은아세틸콜린을포함한기저전뇌(basal forebrain) 로부터영향을받는다(Figure 2). 4 아세틸콜린을분비하는신경은등쪽중뇌와뇌교에있는 pedunculopontine(ppt) 와 laterodorsal tegmental area 6 수면

2 수면각성조절의신경생물학 Figure 1. A drawing of the human brainstem, taken from von Economo's original work. The lesion site of diagonal hatching at the junction of the brainstem and forebrain is caused prolonged sleepiness, and the lesion site of horizontal hatching in the anterior hypothalamus is caused prolonged insomnia. The arrow points to a region between the two, including the posterior lateral hypothalamus. Von Economo suggested that narcolepsy was caused by lesions at this site. (LDT) 에주로위치한다. 5 각성과램수면시활성화되고비램수면때는비활성화되며시상을통한피질활성에관여한다. 기저전뇌에위치하는아세틸콜린은대뇌피질, 해마, 편도(amygdala) 로뻗어있다. 이것은각성시행동상태와관련이있는데만약감소되면뇌파가느려지고인지기능이떨어지게된다. 6 Norepinephrine 은청반(locus coeruleus) 에서주로생성되며대뇌피질, 해마, 시상및시상하부까지뻗어있다. 각성시활성화되며비램수면에서활성이줄어들고램수면에서는비활성화된다. 스트레스상태에서대뇌피질을활성화하고각성을유지하게하는역할을한다. 3 히스타민은시상하부뒤쪽에있는 tuberomammillary nucleus(tmn) 에서주로분비되며뇌전체로뻗어져있다. 각성시활성화되며비램수면에서활성이줄어들고램수면에서는비활성화된다. 기능은각성을조장하고특히깨어날때와높은행동각성이요구되는상황에서작용한다. 세로토인은솔기(raphe) 핵에주로위치하며각성시활성화되며비램수면에서활성이줄어들고램수면에서는비활성화된다. 기능은예전에는각성과수면을모두조장한다고하였는데최근연구에서는각성을조장하는기능이 Figure 2. Some key components of the ascending arousal system. A major ascending pathway (yellow pathway) through the thalamus projects to cerebral cortex. This originates from cholinergic (ACh) cell groups in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). A second pathway (red) activates the cerebral cortex to facilitate the processing of inputs from the thalamus. This arises from neurons in the monoaminergic cell groups, including the tuberomammillary nucleus (TMN) containing histamine (His), the A 10 cell group containing dopamine (DA), the dorsal and median raphe nuclei containing serotonin (5-HT), and the locus coeruleus (LC) containing noradrenaline (NA). 두드려져보이며임상적으로세로토인이감소한우울증환자의경우많이졸리운것을볼수있다. 7 도파민은 substantia nigra, ventral tegmental area 등에위치하여뇌전반에영향을주며, 주로각성을조장한다. 향정신성약물에의해도파민수용체가차단되면졸립게된다. 임상적으로도파민이감소되어있는파킨슨환자에서졸리운증상은흔히볼수있다. 하지만역설적으로도파민길항제에의한졸리운증상도잘알려져있는데이는도파민길항제가자가억제 D2/D3 수용체에결합하여도파민작용을감소시키기때문이다. 8 하이포크레틴/ 올렉신은시상하부의측면과후면에위치한신경에서주로만들어지고중추신경계여러곳 (LC, DR, TMN, PPT, LDT, ventral tegmental area) 으로뻗어져있으며각성을유지하는기능뿐아니라각성과수면을안정화하는데중요한역할을하여원치않는상황에서수면에빠지는것을예방한다. 9 각성시활성화되며, 특히운동활동이높은각성시활성이높다. 오후늦게농도가가장 Vol.3, No.1 / June,

3 조용원 Figure 3. A schematic diagram of the flip-flop switch model. During wakefulness (a), the monoaminergic nuclei (red) inhibit the ventrolateral preoptic nucleus (VLPO; purple), Because the VLPO neurons do not have orexin receptors, the orexin neurons serve primarily to reinforce the monoaminergic tone, rather than directly inhibiting the VLPO on their own. During sleep (b), the firing of the VLPO neurons inhibits the monoaminergic cell groups, thereby relieving their own inhibition. This also allows it to inhibit the orexin neurons, further preventing monoaminergic activation that might interrupt sleep. The direct mutual inhibition between the VLPO and the monoaminergic cell groups forms a classic flip-flop switch, which produces sharp transitions in state, but is relatively unstable. The addition of the orexin neurons stabilizes the switch. 5-HT, serotonin; ACh, cholinergic; evlpo, extended ventrolateral preoptic nucleus; GABA, γ-aminobutyric acid; gal, galanin; LC, locus coeruleus; NA, noradrenaline; PeF, perifornical; TMN, tuberomammillary nucleus. 높아잠들려는욕구에반하여각성을유지하는작용을한다. 10 기면증환자의 90% 에서뇌척수액에서하이포크레틴이감소된소견을보인다. 11 나. 수면과각성에서신경의상호작용 - The flip-flop switch 앞서설명한아세틸콜린, 아민, 하이포크레틴을생성하는신경은각성을조장하는중추이며각각은조금씩다른기능을가지고있지만상호협조하여작용할때완전한각성과피질의활성을보인다. 깨어있는동안모노아민신경은 VLPO(Ventrolateral preoptic area) 를억제하게된다. 하이포크레틴도모노아민신경을도와각성에기여하게된다. 수면동안은 VLPO 신경이모노아민신경을억제하고하이포크레틴도억제한다.VLPO신경과모노아민신경은직접적으로상호억제하여마치시이소처럼 flip-flop switch 를형성하게된다 (Figure 3). 4 이때중간단계는짧아불안정한상태이지만하이포크레틴이안정한상태로유지하는데기여하고있다. Flip-flop switch 모델은각성과수면사이전환이신속하며중간단계인혼미한상태가하루의 1-2% 이하로짧은이유를설명한다. 즉, 우리가별다른경고없이갑자기잠들거나깨어나게되는현상이이러한모델로설명하는데이러한현상은수면과각성상태의빠른적응에는도움이되지만운전중에는갑자기졸음이오는것처럼경고없이갑자기전환됨으로일상생활중에서는상당히위험한상황에직면할수도있다. 2. 수면 - 비램수면및램수면조절계 가. 비램수면 시상하부전방 preoptic area에위치한 VLPO신경이수면, 특히비램수면을생성하는데필수적이다. 억제성신경전달물질인 GABA 와 galanin 를통해 TMN, 외측시상하부,LC,DR,LDT/PPT 에억제성영향을나타낸다. 12 나. 램수면 램수면은콜린성과아민성신경의상호작용에의해조절된다. 램수면동안뇌교의등쪽에위치한 LDT/PPT 신경은시상으로콜린을분비하여위로는시상을흥분시키며피질의비동기화를유발한다. 13 각성및비램수면동안이신경은 NE, 5-HT, HA 신경에의해억제된다. LDT/PPT 신경의아래쪽경로는 ACH, glutamate를분비하여연수에작용하며연수에서 glycine 를통해운동신경에작용하여램수면동안근육긴장을저하시키는역할을한다. 14 또한연수는청반(LC) 과적색핵(red nucleus) 에서나오는흥분성신호를약화시켜근육의긴장을줄인다. 15 램수면때근육긴장이떨어지는것은이렇게직접적인영향및간접적인영향이함께작용하기때문이다. 기면증에있어서삼환계항우울제및기타항우울제의작용기전은아민성신경을조장하여램수면을줄이고직접적으로운동신경을흥분시키기때문이다 수면

수면각성조절의신경생물학 Figure 4. A schematic diagram to illustrate the three stage integrator for circadian rhythm. The suprachiasmatic nucleus (SCH) serves as a biological clock.

4 수면각성조절의신경생물학 Figure 4. A schematic diagram to illustrate the three stage integrator for circadian rhythm. The suprachiasmatic nucleus (SCH) serves as a biological clock. Most of its output goes into the region in light brown, which includes the ventral (vspz) and dorsal (dspz) subparaventricular zone, and the dorsomedial nucleus of the hypothalamus (DMH). Neurons in the vspz relay information necessary for organizing daily cycles of wake-sleep, whereas dspz neurons are crucial for rhythms of body temperature. Outputs from the SPZ are integrated in the DMH with other inputs, and DMH neurons drive circadian cycles of sleep, activity, feeding and corticosteroid secretion, Cycles of body temperature are maintained by dspz projections back to the medial preoptic area (MPO), whereas the DMN is the origin of projections to the VLPO for sleep cycles, to the corticotropin-releasing hormone (CRH) neurons of the paraventricular nucleus (PVH) for corticosteroid cycles, and to the lateral hypothalamic (LHA) orexin and melaninconcentrating hormone neurons for wakefulness and feeding cycles. 3. 수면 - 각성의동력학 수면의기능중의하나는뇌의회복기능이다.Borbely 등은수면과각성을조절하는데있어항상성 (homeostatic; process S) 과일주기(circadian; process C) 리듬의상호작용모델을제시하였다. 17 다른항상성시스템처럼수면도부족하게되면이를보충하기위해수면시간이늘어나게된다. 이러한항상성요소는깨어있을때축적되고수면중감소된다. 이것은일주기계와함께작용하여수면을조절한다. 신체는오랫동안깨어있으면내부에서수면을조장하는물질이나오게되는데이를 somnogen이라고하며 adenosine 과 cytokine 등이여기에속하며, 각성시간이오래지속됨에따라점차체내에축적되어수면을촉진한다. 18 이중adenosine 은오래깨어있는동안뇌에서에너지, 즉 ATP 가대사되어 AMP 를거쳐생성되며 VLPO 의신경을자극하여수면을조장한다. 19 병적으로도발작, 저혈당및뇌경색등에서도생성이증가된다. 우리가마시는커피의각성효과는이 adenosine 수용체를차단함으로나타난다. Interleukin- 1 와tumor necrosis factor-α 같은 cytokine 은prost - aglandin 합성을통해램수면과비램수면을조장한다. 20 일주기계는 24시간의주기를나타내는신체시계를가리킨다. 상부시각교차핵(suprachiasmatic nucleus) 는 ventral (vspz) 와 dorsal(dspz) supraventricular zone를통해시상하부내측 (dorsomedial nucleus of the hypothalamus, DMH) 에작용하여행동과내분비기능을조절하며각성과수면의 circadian 리듬을조절하게된다. 이때 vspz는각성- 수면사이클과관련되며, dspz은체온의리듬에관여한다. 21 DMH는 VLPO 를통해수면에, paraventricular nucleus(pvh) 를통해피질호르몬분비에, lateral hypothalamus(lha) 를통해올렉신과멜라토인을분비하여각성과식욕조절에관여한다 (Figure 4). 4 낮동안망막을통해받는빛의신호와밤동안송과체에서분비되는멜라토인에의해 suprachiasmatic nucleus이셋팅이된다. 이러한시간신호는외부의낮과밤의사이클과일치하게된다 (Figure5). SPZ과 DMH 의통합단계는외부의자극에영향을받는데, 외부자극에는음식, 내장감각, 인지및감정등이있다. 음식이위장관에들어가면고립로(solitary tract) 를통해서내장감각이전달되어졸음이생기며공복시에는각성이생기게된다. 그래서 DMH 는이러한외부자극에대한통합하여환경과생리적주기에유연하게하여생존의가능성을높인다. 22 수면과각성의조절에는많은신경들의복잡한상호작용으로이루어진다. 수면동안은과거생각과달리눈을감고움직이지않고있지만신체내에서는생물학적활동이활발하고대사속도도높다. 그래서수면은낮동안의신체적건강과도직결될뿐아니라인지기능등의정신적인건강과도관련이있다. 현재많은질병들이숙면을취하지못 Vol.3, No.1 / June,

5 조용원 해생기거나, 혹은반대로여러가지질병으로인해숙면을취하지못하고있다. 또한임상에서사용하는많은약물들이수면에영향을미치고있어수면에대한올바른이해는신체의건강을유지하고다른질환을예방하거나치료하는데도도움이된다. 최근수면의학이많은관심을가지게되고연구되고있지만아직까지많은부분이밝혀져있지않은상태이다. 향후수면과각성의기초에관한완전한이해를위해서는많은연구들이필요하겠으며이는나아가낮동안건강한신체를유지하는데도이바지할것으로기대된다. REFERENCES 1. Von Economo, C. Sleep as a problem of localization. JNervMent Dis 1930;71: Jones BE. Basic mechanisms of sleep-wake states. In: Kryger MH, Roth T, and Dement WC, eds, Principles and practice of sleep medicine, 4 th Ed. Philadelphia, WB Saunders: 2005: Espana RA, Scammell TE. Sleep neurobiology for the clinician. Sleep 2004;27: Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437: Hallanger, AH, Levey, AI, Lee, HJ, Rye, DB & Wainer, BH The origins of cholinergic and other subcortical afferents to the thalamus in the rat. JCompNeurol1987;262: Ray PG, Jackson WJ. Lesions of nucleus basalis alter ChAT activity and EEG in rat frontal neocortex. Electroencephalogr Clin Neurophysiol 1991;79: McGrath PJ, Stewart JW, Janal MN, Petkova E, Quitkin FM, Klein DF. A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical depression. Am J Psychiatry 2000;157: Lagos P, Scorza C, Monti JM, et al. Effects of the D3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats. Eur Neuropsychopharmacol 1998;8: Peyron C, Tighe DK, van Den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18: Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J Neurosci 2003;23: Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59: Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 1998;18: Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci 2002;16: Curtis DR, Hosli L, Johnston GA, Johnston IH. The hyperpolarization of spinal motoneurones by glycine and related amino acids. Exp Brain Res 1968;5: Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Cessation of activity in red nucleus neurons during stimulation of the medial medulla in decerebrate rats. JPhysiol2002;545: Kubin L, Tojima H, Davies RO, Pack AI. Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat. Neurosci Lett 1992;139: Borbely AA, Achermann P. Concepts and models of sleep regulation: an overview. J Sleep Res 1992;1: Ishimori K. True cause of sleep: A hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi 1909;23: Porkka-Heiskanen, T, Strecker, RE & McCarley, RW Brain sitespecificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 2000;99: Hayaishi O, Urade Y. Prostaglandin D2 in sleep-wake regulation: recent progress and perspectives. Neuroscientist 2002;8: Lu J, Zhang YH, Chou TC, et al. Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation. J Neurosci 2001;21: Saper, CB, Lu, J, Chou, TC & Gooley, J. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005;28: 수면

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Microsoft Word doc KISEP Overview 대한정신약물학회지 : 제 18 권제 3 호 2007 수면 - 각성조절의신경해부학과그의약물치료적적용 ABSTRACT 김희철 계명대학교의과대학정신과학교실, 계명대학교동산의료원수면클리닉 Neuroanatomy of Sleep-Wake Regulation and its Application to Pharmacotherapy Hee-Cheol