臂旁核神經(jīng)元調(diào)節(jié)睡眠覺(jué)醒的研究進(jìn)展

趙敏銳，王典茹，楊解人，王毅群

(1. 皖南醫(yī)學(xué)院藥理學(xué)教研室，安徽 蕪湖　241000、2. 復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系，上?！?00032)

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臂旁核神經(jīng)元調(diào)節(jié)睡眠覺(jué)醒的研究進(jìn)展

趙敏銳1，王典茹2，楊解人1，王毅群2

(1. 皖南醫(yī)學(xué)院藥理學(xué)教研室，安徽 蕪湖241000、2. 復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系，上海200032)

摘要：臂旁核(parabrachial nucleus, PB)是環(huán)繞在腦橋結(jié)合臂周?chē)幕屹|(zhì)結(jié)構(gòu)，主要由谷氨酸、γ-氨基丁酸(γ-aminobutyric acid, GABA)和腦啡肽神經(jīng)元組成。PB與下丘腦、基底前腦等覺(jué)醒核團(tuán)有著廣泛的神經(jīng)纖維聯(lián)系，特異性損毀PB可引起動(dòng)物昏迷樣癥狀。同時(shí)，PB向非快動(dòng)眼(non-rapid eye movement，NREM)睡眠核團(tuán)腹內(nèi)側(cè)視前區(qū)投射，并接受來(lái)自面旁核的投射，激活面旁核中的GABA能神經(jīng)元可促進(jìn)NREM睡眠，表明PB可能參與NREM睡眠的調(diào)控。此外，快動(dòng)眼(rapid eye movement，REM)睡眠剝奪會(huì)引起臂旁外側(cè)核的興奮。綜上所述，PB在機(jī)體調(diào)節(jié)覺(jué)醒、NREM和REM睡眠中發(fā)揮著重要作用。該文將就PB在睡眠-覺(jué)醒調(diào)節(jié)作用中的研究進(jìn)展做一綜述。

關(guān)鍵詞：臂旁核；覺(jué)醒；非快動(dòng)眼睡眠；快動(dòng)眼睡眠；谷氨酸神經(jīng)元；投射

人生的三分之一在睡眠中度過(guò)，睡眠相分為快動(dòng)眼(rapid eye movement, REM)睡眠和非快動(dòng)眼(non-rapid eye movement, NREM)睡眠，所有的哺乳動(dòng)物、鳥(niǎo)類(lèi)和爬行動(dòng)物都需要睡眠。睡眠不僅僅是正常的生理行為，更是保障精力充沛的先決條件。當(dāng)今社會(huì)，隨著經(jīng)濟(jì)發(fā)展和競(jìng)爭(zhēng)壓力的增大，睡眠障礙問(wèn)題愈發(fā)嚴(yán)重，臨床缺乏有效治療手段，原因在于睡眠覺(jué)醒機(jī)制未明。已探知的覺(jué)醒核團(tuán)包括中腦中縫背核(dorsal raphe nucleus，DRN)[1]、腦橋藍(lán)斑核(locus coeruleus，LC)[2]、下丘腦結(jié)節(jié)乳頭核(tuberomammillary nucleus，TMN)[3-4]、外側(cè)下丘腦( lateral hypothalamus，LH)[5]等，而睡眠核團(tuán)包括腹外側(cè)視前區(qū)(ventrolateral preoptic，VLPO)[6]和面神經(jīng)旁核(parafacial zone，PZ)[7]等，睡眠與覺(jué)醒核團(tuán)既相互對(duì)立又緊密聯(lián)系，共同調(diào)控睡眠覺(jué)醒。

臂旁核(parabrachial nucleus, PB)最早發(fā)現(xiàn)于1914年，位于腦橋背側(cè)部，小腦腳(腦橋結(jié)合臂)周?chē)?，后被Taber首次命名為“結(jié)合臂旁核”，與下丘腦、丘腦、基底前腦、大腦皮層、腹內(nèi)側(cè)視前區(qū)和面神經(jīng)旁核等核團(tuán)有著廣泛的神經(jīng)纖維聯(lián)系。1984年，Saper等將PB劃分為臂旁外側(cè)核(the lateral parabrachial nucleus, LPB)、臂旁內(nèi)側(cè)核(the medial parabrachial nucleus, MPB)和KF核 (Kolliker-Fuse nucleus)3個(gè)亞核團(tuán)。其中LPB又可分為7個(gè)亞核，即上外側(cè)核(superior lateral nucleus, LPBs)、內(nèi)外側(cè)核(internal lateral nucleus, LPBi)、中央外側(cè)核(central lateral nucleus, LPBc)、背外側(cè)核(dorsal lateral nuleus, LPBd)、腹外側(cè)核(ventral lateral nucleus, LPBv)、極外側(cè)核(extreme lateral nucleus，LPBel)和外外側(cè)核(external lateral nucleus，LPBexl)。MPB分為兩個(gè)亞核，即內(nèi)側(cè)臂旁核(medial parabrachilal nucleus，MPB)和外內(nèi)側(cè)亞核(external medial subnucleus，MPBe)[8]。PB作為腦橋部重要的中樞信號(hào)傳遞核團(tuán)，參與調(diào)節(jié)機(jī)體多項(xiàng)生理功能：傳導(dǎo)至PB的γ-氨基丁酸(γ-aminobutyric acid，GABA)能投射促進(jìn)動(dòng)物攝食，而傳導(dǎo)至PB的谷氨酸能投射則抑制動(dòng)物攝食[9]，這表明PB可能調(diào)節(jié)晝夜規(guī)律進(jìn)食；PB向視前區(qū)的投射可能控制溫度感受，因?yàn)楹笳咭种票硟?nèi)側(cè)下丘腦中與產(chǎn)熱相關(guān)神經(jīng)元[10]；PB還可能參與了痛覺(jué)傳導(dǎo)和調(diào)節(jié)，脊髓接受來(lái)自外周的疼痛感受纖維傳入，并通過(guò)PB傳出至疼痛相關(guān)的導(dǎo)水管灰質(zhì)(periaqueopctal gray，PAG)、下丘腦和杏仁核等[11-12]，因此，我們推斷PB可能是脊髓向其他疼痛相關(guān)核團(tuán)傳導(dǎo)的中轉(zhuǎn)站；PB參與了呼吸調(diào)節(jié)，其LPBexl和LPBc亞核中的谷氨酸能神經(jīng)元可促使睡眠呼吸暫停動(dòng)物覺(jué)醒，Kaur等的實(shí)驗(yàn)表明，PB中谷氨酸能神經(jīng)元與機(jī)體對(duì)CO2感受有關(guān)，而PB中谷氨酸能神經(jīng)元與BF、LH、丘腦和皮層等覺(jué)醒核團(tuán)纖維聯(lián)系緊密[13-14]，由此推斷，PB中谷氨酸能神經(jīng)可能同時(shí)調(diào)控了睡眠覺(jué)醒與呼吸?？偨Y(jié)可知，以上這些生理功能多具有睡眠覺(jué)醒的節(jié)律性，進(jìn)而提示我們：PB可能參與調(diào)控睡眠覺(jué)醒。特異性損毀PB引起動(dòng)物昏迷，證明了以上結(jié)論[15]。因此，本文主要論述PB與睡眠覺(jué)醒作用之間的聯(lián)系。

1PB與覺(jué)醒系統(tǒng)

覺(jué)醒是大腦中覺(jué)醒系統(tǒng)介導(dǎo)的皮層興奮，是生物正?；顒?dòng)的基礎(chǔ)，這種興奮依賴于上行網(wǎng)狀興奮系統(tǒng)的活動(dòng)維持[16]。1949年，Moruzzi將貓中腦和腦橋的網(wǎng)狀部毀損，貓持續(xù)昏迷，提示我們：中腦和腦橋網(wǎng)狀部中的核團(tuán)與覺(jué)醒啟動(dòng)密切相關(guān)。2011年，F(xiàn)uller等[15]雙側(cè)毀損PB，發(fā)現(xiàn)動(dòng)物陷入昏迷，表明PB可能是覺(jué)醒系統(tǒng)的關(guān)鍵核團(tuán)。此后，PB與覺(jué)醒的關(guān)系受到睡眠研究者們的重視。而PB中谷氨酸能神經(jīng)元作為其最主要的興奮性神經(jīng)遞質(zhì)[17]，與基底前腦(basal forebrain, BF)、LH、丘腦、DRN及大腦皮層等聯(lián)系都十分緊密。

BF與皮層之間的神經(jīng)纖維投射十分密集，是大腦維持覺(jué)醒的重要核團(tuán)[7,18]。離體膜片鉗實(shí)驗(yàn)表明：激活PB中谷氨酸能神經(jīng)元的軸突末梢，可在基底前腦神經(jīng)元上檢測(cè)到谷氨酸能電流，并且這些神經(jīng)元投向皮層，證明興奮PB向BF投射的谷氨酸能神經(jīng)元可以興奮BF向皮層投射的谷氨酸能神經(jīng)元[7,19-20]；在體實(shí)驗(yàn)表明：損毀BF可導(dǎo)致皮層興奮性降低，動(dòng)物反應(yīng)遲鈍；而損毀PB會(huì)使動(dòng)物昏迷，皮層興奮性降低。上述結(jié)果提示：PB向BF的谷氨酸能投射是維持覺(jué)醒的重要因素[15]。損毀PB可能切斷了MPB中谷氨酸能神經(jīng)元向BF的投射，導(dǎo)致皮層興奮性降低，難以維持大腦皮層覺(jué)醒，使動(dòng)物陷入昏迷。

現(xiàn)階段研究表明，LPB中的谷氨酸能神經(jīng)元可能是LH中食欲肽(orexin)能神經(jīng)元的重要興奮來(lái)源。下丘腦orexin能神經(jīng)元的興奮是維持覺(jué)醒的基礎(chǔ)，orexin的合成只存在于LH的神經(jīng)元中[21]。在覺(jué)醒期，動(dòng)物下丘腦orexin分泌量明顯增多[22]，orexin能神經(jīng)元的c-Fos蛋白表達(dá)增強(qiáng)[5]，放電頻率增高；但在REM和NREM睡眠期，放電幾乎停止[23]。神經(jīng)解剖學(xué)研究顯示：LPB中谷氨酸能神經(jīng)元的纖維末梢與LH的orexin能神經(jīng)元胞體形成突觸聯(lián)系，這表明LH中的orexin能神經(jīng)元接受來(lái)自LPB中的谷氨酸能神經(jīng)元的投射[24]。由以上實(shí)驗(yàn)結(jié)果推測(cè)：LPB中的谷氨酸能神經(jīng)元可能通過(guò)興奮LH中的orexin能神經(jīng)元，增加orexin，維持皮層興奮。

PB的促覺(jué)醒作用可能與上行網(wǎng)狀興奮系統(tǒng)有關(guān)。上行網(wǎng)狀興奮系統(tǒng)包括背側(cè)和腹側(cè)兩條通路，這兩條通路都可以將腦干興奮傳遞到皮層。在上行網(wǎng)狀興奮系統(tǒng)的背側(cè)通路中，與覺(jué)醒相關(guān)的中腦、腦橋和延髓網(wǎng)狀結(jié)構(gòu)的興奮性可以通過(guò)丘腦中線核和丘腦髓板內(nèi)核傳遞到丘腦-皮層投射系統(tǒng)[25-28]。PB谷氨酸能神經(jīng)元向丘腦中線核投射[15]，因此，我們推斷PB可能通過(guò)上行網(wǎng)狀興奮系統(tǒng)的背側(cè)通路作用于皮層，誘發(fā)皮層興奮。

DRN中5-HT能神經(jīng)元可能是PB介導(dǎo)覺(jué)醒的另一途徑。成年貓?jiān)谟X(jué)醒期DRN中5-HT濃度明顯增高，5-HT能神經(jīng)元放電頻率升高，在NREM期放電頻率降低[1,29]；在大鼠DRN內(nèi)微量注射對(duì)氯苯丙氨酸(p-chlorophenylalanine，PCPA)選擇性的抑制5-HT的生物合成后，出現(xiàn)覺(jué)醒減少的效應(yīng)[30]，以上實(shí)驗(yàn)證明DRN中5-HT與覺(jué)醒相關(guān)。逆向追蹤DRN中5-HT能神經(jīng)元接受的投射發(fā)現(xiàn)，這些投射來(lái)源于MPB和LPB的谷氨酸能神經(jīng)元。由此推斷，興奮PB中的谷氨酸能神經(jīng)元可以興奮DRN中的5-HT能神經(jīng)元，使其發(fā)揮促覺(jué)醒作用[31]。

綜上所述，PB中的谷氨酸能神經(jīng)元通過(guò)細(xì)胞間的神經(jīng)纖維聯(lián)系，將興奮傳導(dǎo)到 BF、LH、丘腦和DRN等，激活這些核團(tuán)，產(chǎn)生促覺(jué)醒作用。此外，PB中的谷氨酸能神經(jīng)元也可直接興奮皮層，誘導(dǎo)覺(jué)醒[15]。

2PB和NREM睡眠系統(tǒng)

腹外側(cè)視前區(qū)(ventrolateral preoptic，VLPO)是重要的睡眠促進(jìn)核團(tuán)。2008年，Greco等[6]發(fā)現(xiàn)，VLPO接受來(lái)自LPBc腦啡肽神經(jīng)元的投射，并且在VLPO中灌流阿片受體激動(dòng)劑，可增加NREM睡眠。由上述實(shí)驗(yàn)推測(cè)，VLPO促 NREM睡眠作用可能是由LPBc中的腦啡肽神經(jīng)元介導(dǎo)的。

此外，通過(guò)免疫雙標(biāo)法對(duì)貓腦細(xì)胞活性研究發(fā)現(xiàn)：在NREM睡眠期，LPBc核團(tuán)中的c-Fos蛋白表達(dá)明顯增強(qiáng)，并且c-Fos陽(yáng)性點(diǎn)能與GABA能神經(jīng)元共標(biāo)，證明LPBc中GABA能神經(jīng)元在NREM睡眠期被興奮，提示LPBc的GABA能神經(jīng)元很可能發(fā)揮促NREM睡眠作用[32]。

最新研究提示：PB調(diào)控NREM睡眠的機(jī)制可能與面神經(jīng)旁核(parafacial zone，PZ)密切相關(guān)。NREM睡眠期，PZ的c-Fos蛋白表達(dá)明顯增加；毀損PZ會(huì)導(dǎo)致動(dòng)物持續(xù)的覺(jué)醒；使用DREADD(designer receptors exclusively activated by a designer drug)技術(shù)，特異性激活PZ的GABA能神經(jīng)元，會(huì)增加NREM睡眠，提示PZ參與調(diào)節(jié)NREM睡眠[7]。解剖學(xué)研究表明，PZ中GABA/甘氨酸能神經(jīng)元向PB密集投射[33]；電生理結(jié)果顯示，PZ中GABA能神經(jīng)元抑制PB向BF的興奮性投射[7]。上述結(jié)果提示：PB介導(dǎo)了PZ對(duì)NREM睡眠和皮層興奮性的調(diào)控。

以上結(jié)果表明：PB不僅是促覺(jué)醒核團(tuán)，同時(shí)還參與了NREM睡眠的調(diào)控。PB調(diào)控睡眠的其中一條通路是作用于促NREM睡眠核團(tuán)VLPO調(diào)控睡眠。另一條通路是PB接收來(lái)自PZ的抑制性投射，間接抑制BF和皮層的興奮性，發(fā)揮促睡眠作用。

3PB和REM睡眠系統(tǒng)

PB不僅參與了覺(jué)醒和NREM睡眠調(diào)節(jié)，還可能與REM睡眠相關(guān)。實(shí)驗(yàn)證明，動(dòng)物REM睡眠剝奪后，機(jī)體會(huì)產(chǎn)生代償作用，進(jìn)而增加REM睡眠[34]。對(duì)REM睡眠剝奪動(dòng)物進(jìn)行c-Fos染色發(fā)現(xiàn)，LPB各亞區(qū)的c-Fos蛋白表達(dá)明顯增多，尤其集中在LPBc中，而MPB中c-Fos陽(yáng)性點(diǎn)沒(méi)有明顯增加[35]；但損毀MPB會(huì)使動(dòng)物REM睡眠增加[15]，由以上實(shí)驗(yàn)說(shuō)明，PB參與調(diào)控REM睡眠。

此外，PB可能介導(dǎo)了背外側(cè)被蓋核(sublaterodorsal tegmental nucleus，SLD)向BF的投射，這可能是REM睡眠時(shí)皮層興奮的主要原因[36]。REM睡眠剝奪時(shí)，SLD中80%的谷氨酸能神經(jīng)元興奮，表明SLD的谷氨酸能神經(jīng)元參與REM睡眠的調(diào)節(jié)，而MPB接受來(lái)自SLD谷氨酸能神經(jīng)元的投射[37]，并可通過(guò)BF調(diào)控皮層興奮性[7]，因此，PB可能介導(dǎo)了SLD對(duì)REM睡眠的調(diào)節(jié)作用。

腹外側(cè)導(dǎo)水管灰質(zhì)(ventrolateral periaqueopctal gray，vlPAG)是REM睡眠抑制核團(tuán)，毀損vlPAG會(huì)引起REM睡眠的增加。vlPAG接受來(lái)自SLD的抑制性GABA能投射，并通過(guò)其GABA能神經(jīng)元抑制下游PB區(qū)，這可能是機(jī)體控制REM睡眠中的一條通路[15]。

PB介導(dǎo)REM睡眠和覺(jué)醒的進(jìn)程均投射至BF，由此猜想：在覺(jué)醒期，PB谷氨酸能投射并興奮BF，進(jìn)而興奮大腦皮層，產(chǎn)生覺(jué)醒效應(yīng)；在REM睡眠期，REM睡眠促進(jìn)核團(tuán)SLD中谷氨酸神經(jīng)和REM睡眠抑制核團(tuán)vlPAG中GABA能神經(jīng)元通過(guò)上述覺(jué)醒通路作用于皮層，調(diào)節(jié)REM睡眠，并產(chǎn)生REM睡眠效應(yīng)。

4小結(jié)

PB是位于腦橋部的中轉(zhuǎn)核團(tuán)，參與機(jī)體多項(xiàng)生理功能的調(diào)節(jié)，同時(shí)負(fù)責(zé)錯(cuò)綜復(fù)雜的睡眠覺(jué)醒信號(hào)的傳遞，調(diào)控覺(jué)醒、NREM和REM睡眠，但由于其調(diào)控的生理功能多具有睡眠覺(jué)醒節(jié)律性，我們因此推斷：PB中某些神經(jīng)元同時(shí)調(diào)控睡眠與覺(jué)醒這些生理功能；此外，PB中的谷氨酸能神經(jīng)元是維持覺(jué)醒的主要因素，并向下丘腦、中腦、丘腦、基底前腦、大腦皮層等廣泛投射，以上事實(shí)表明PB可能參與上行興奮系統(tǒng)；PB的部分區(qū)域具有調(diào)節(jié)NREM睡眠的作用，并介導(dǎo)了PZ對(duì)NREM睡眠的調(diào)控，這可能是PZ間接抑制PB下游促覺(jué)醒核團(tuán)的結(jié)果；PB參與調(diào)控REM睡眠的機(jī)制可能是SLD、vlPAG等REM核團(tuán)通過(guò)PB的覺(jué)醒通路對(duì)皮層作用。綜上可知，PB調(diào)節(jié)睡眠覺(jué)醒網(wǎng)絡(luò)極其復(fù)雜，因此，本文將PB參與調(diào)控睡眠-覺(jué)醒核團(tuán)的神經(jīng)網(wǎng)絡(luò)進(jìn)行了梳理、總結(jié)和歸納,如Fig 1。

Fig 1　Connection of the PB with sleep-wake regulation systems

PB sends projections to cerebral cortex, wake-related nuclei including BF, LH, Thalamus, DRN, etc., and to NREM-related nuclei including VLPO. Meanwhile, PB also receives afferents from REM-related SLD and vlPAG, NREM-related PZ. The glutamatergic neurons in PB project to cerebral cortex, BF, LH, Thalamus and DRN, while opioid neurons to VLPO. PB also receives GABA afferents from PZ and vlPAG, glutamatergic projections from SLD. The black, blue and red circles represent wake-, NREM- and REM-related nucleis, respectively. The arrow represents afferent projection. The line represents efferents. PB, parabrachial nucleus; BF, basal forebrain; VLPO, ventrolateral preoptic nucleus; LH, lateral hypothalamus; SLD, sublaterodorsal tegmental nucleus; vlPAG, ventrolateral periaqueopctal gray; DRN, dorsal raphe nucleus; PZ, parafacial zone.

5展望

PB在睡眠覺(jué)醒調(diào)控中的重要性日益明確，但其與睡眠覺(jué)醒核團(tuán)之間的纖維聯(lián)系對(duì)睡眠覺(jué)醒的調(diào)控仍處于推論階段，需要更加直接的證據(jù)予以證明；PB自身亞區(qū)結(jié)構(gòu)復(fù)雜，各亞區(qū)對(duì)睡眠覺(jué)醒的作用并不完全清楚；PB中神經(jīng)元具有異質(zhì)性，這些不同神經(jīng)元對(duì)睡眠覺(jué)醒的調(diào)節(jié)作用也不明確；PB與其他神經(jīng)核團(tuán)及環(huán)路間關(guān)系網(wǎng)絡(luò)龐大，目前的研究仍有許多未探明之處，需要更多科研資源的投入。但隨著科技的進(jìn)步，社會(huì)的發(fā)展，相信人類(lèi)終將能解決這些問(wèn)題。

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Regulatory effects of PB on sleep and wakefulness

ZHAO Min-rui1, WANG Dian-ru2,YANG Jie-ren1,WANG Yi-qun2

(1.DeptofPharmacology,WannanMedicalCollege,WuhuAnhui241000,China;2.DeptofPharmacology,BasicMedicalCollege,FudanUniversity,Shanghai200032,China)

Abstract:The parabrachial nucleus (PB) is made up of gray matter around the Pons combination(BC), mainly consisting of glutamatergic, GABAergic and enkephalinergic neurons. PB is connected to hypothalamus and basal forebrain through a network of nerve fibers. Specific lesion of the entire parabrachial complex in animals leads to a deep coma. PB also projects to the non-rapid eye movement(NREM)-related regions including the ventrolateral preoptic, and receives the projections from the parafacial zone. Activation of the GABAergic neurons in parafacial zone can promote NREM sleep, which indicates that PB participates in NREM sleep. Furthermore, the lateral PB is actived when rapid eye movement(REM) sleep is deprived. In conclusion, PB participates in regulating wakefulness, NREM and REM sleep. This review summarizes the advances in the roles of PB in sleep-wake regulation.

Key words:parabrachial nucleus; wakefulness; NREM sleep; REM sleep;glutamatergic neuron;projection

收稿日期:2016-01-11,修回日期:2016-02-14

基金項(xiàng)目：國(guó)家自然科學(xué)基金面上項(xiàng)目(No 81571295)

作者簡(jiǎn)介：趙敏銳(1990 -),男,碩士生,研究方向:臨床藥理學(xué),E-mail:15601912979@163.com;

doi:10.3969/j.issn.1001-1978.2016.06.006

文獻(xiàn)標(biāo)志碼：A

文章編號(hào)：1001-1978(2016)06-0764-04

中國(guó)圖書(shū)分類(lèi)號(hào)：R-05；R322.81；R338.63

網(wǎng)絡(luò)出版時(shí)間：2016-5-25 15:39網(wǎng)絡(luò)出版地址：http://www.cnki.net/kcms/detail/34.1086.R.20160525.1539.012.html

楊解人(1955 - ),女,教授,碩士生導(dǎo)師,研究方向:臨床藥理學(xué),通訊作者,E-mail: jryang1955@sina.com;

王毅群(1982 - ),女,博士,副教授,研究方向:睡眠醫(yī)學(xué), 通訊作者, E-mail: 061101069@fudan.edu.cn