表觀遺傳修飾在應(yīng)激誘發(fā)抑郁癥中的作用*

(中國科學(xué)院心理健康重點(diǎn)實(shí)驗(yàn)室,中國科學(xué)院心理研究所,北京 100101)(中國科學(xué)院大學(xué),北京 100049)

抑郁癥是現(xiàn)代社會(huì)嚴(yán)重的精神衛(wèi)生問題,作為一種慢性傾向的精神疾病,其臨床表現(xiàn)為心境低落、快感缺失、意志活動(dòng)減退、認(rèn)知功能損害,甚至出現(xiàn)自殺行為。隨著生活節(jié)奏的加快,學(xué)習(xí)、就業(yè)、工作壓力的增大,競(jìng)爭(zhēng)加劇,精神壓力也隨之增大,抑郁癥的發(fā)病率呈逐年增高的趨勢(shì),已成為危害人類健康的常見病。世界衛(wèi)生組織統(tǒng)計(jì)發(fā)現(xiàn),抑郁癥已成為世界第四大疾病,并預(yù)測(cè)到2030年抑郁癥將成為全球第二大疾病(M athers&Loncar,2006)。抑郁癥是由先天的遺傳和后天的環(huán)境因素共同作用的結(jié)果。從環(huán)境因素角度,應(yīng)激,特別是慢性應(yīng)激和生命早期應(yīng)激是誘發(fā)抑郁癥的重要因素。人類研究報(bào)道,孕期感染、經(jīng)濟(jì)狀況惡化、社會(huì)支持缺乏、經(jīng)歷屠殺事件、發(fā)育早期的童年受虐等生活負(fù)性事件都屬于誘發(fā)抑郁癥的環(huán)境因素(Lopizzo etal.,2014)。在動(dòng)物研究方面,已通過急、慢性應(yīng)激的方法建立了多種有效抑郁癥模型(Krishnan&Nestler,2011)。應(yīng)激致抑郁癥的機(jī)制的研究涉及神經(jīng)內(nèi)分泌學(xué)說、單胺類遞質(zhì)學(xué)說、神經(jīng)免疫學(xué)說、神經(jīng)可塑性和腦源性神經(jīng)生長(zhǎng)因子學(xué)說等(Gold,2015;Pechtel&Pizzagalli,2011)。盡管大量研究發(fā)現(xiàn)應(yīng)激誘發(fā)了機(jī)體多個(gè)系統(tǒng)的生物學(xué)異常,但抑郁癥的病因機(jī)制迄今仍難清楚闡明。近年來,表觀遺傳機(jī)制的研究受到科學(xué)家的密切關(guān)注。表觀遺傳從基因與環(huán)境交互作用角度研究應(yīng)激對(duì)人類行為的影響(Farrell&O'Keane,2016;Lockwood,Su&Youssef,2015),強(qiáng)調(diào)環(huán)境因素引起基因的表觀遺傳修飾發(fā)生變化,在不改變基因組序列的情況下對(duì)基因轉(zhuǎn)錄進(jìn)行調(diào)控,從而影響生理和行為。這為抑郁癥的病因?qū)W研究開辟了新的方向。本文從下丘腦－垂體－腎上腺軸(hypothalam ic-pituitary-adrenalaxis,HPA)、單胺類遞質(zhì)、腦源性神經(jīng)營(yíng)養(yǎng)因子(brain derived neurotrophic factor,BDNF)三個(gè)方面綜述表觀遺傳修飾在應(yīng)激誘發(fā)抑郁癥中的作用。

1 表觀遺傳機(jī)制簡(jiǎn)介

表觀遺傳(epigenetics)是指DNA序列不發(fā)生變化,但基因表達(dá)卻發(fā)生了可遺傳的改變(Delcuve,Rastegar,&Davie,2009)。研究發(fā)現(xiàn)該機(jī)制主要有:DNA甲基化、組蛋白修飾、染色質(zhì)重塑、基因組印記和非編碼RNA等。目前在心理應(yīng)激方面的研究主要集中在DNA甲基化、組蛋白修飾兩方面。

DNA甲基化主要發(fā)生于DNA的CpG兩個(gè)核苷酸,在DNA甲基轉(zhuǎn)移酶(DNAmethyltransferase,DNMT)的催化下,胞嘧啶的第五位碳原子被添加甲基,形成5-甲基胞嘧啶。DNA甲基化能改變?nèi)旧|(zhì)結(jié)構(gòu)、DNA構(gòu)象及DNA與蛋白質(zhì)相互作用方式,從而在基因轉(zhuǎn)錄中發(fā)揮抑制作用。一般認(rèn)為基因啟動(dòng)子區(qū)的DNA甲基化水平升高,則基因轉(zhuǎn)錄抑制;DNA甲基化水平降低,則基因轉(zhuǎn)錄增強(qiáng)(Bagot,Labonté,Pe?a,&Nestler,2014;Menke,K lengel,&Binder,2012)。

組蛋白是核小體(染色體基本結(jié)構(gòu))中的重要組成部分。組蛋白修飾是指組蛋白在相關(guān)酶催化下,其N末端氨基酸殘基發(fā)生甲基化、乙酰化、磷酸化、腺苷酸化、泛素化、ADP核糖基化等共價(jià)修飾的過程。組蛋白的修飾可以通過改變組蛋白與DNA雙鏈的親和性,從而影響染色質(zhì)的疏松或凝集狀態(tài),進(jìn)而調(diào)控基因轉(zhuǎn)錄。其中,組蛋白甲基化、乙?；芯孔疃?。組蛋白乙?；饕l(fā)生在組蛋白N末端的賴氨酸殘基上,是由組蛋白乙酰轉(zhuǎn)移酶(histone acetyltransferase,HAT)和組蛋白去乙?；?histone deacetylase,HDAC)共同維持。一般情況下,組蛋白乙?；诨蜣D(zhuǎn)錄激活中發(fā)揮作用。組蛋白的賴氨酸和精氨酸殘基的甲基化是由組蛋白甲基化轉(zhuǎn)移酶(histonemethyl transferase,HMT)完成的。賴氨酸可以被一、二、三甲基化,精氨酸只能被一、二甲基化。一般情況下,H3K 4甲基化和H3K36甲基化與基因轉(zhuǎn)錄激活有關(guān),H3K 9甲基化和H3K27甲基化與基因轉(zhuǎn)錄抑制有關(guān)(Bagotetal.,2014;Menke etal.,2012)。

2 表觀遺傳修飾在應(yīng)激誘發(fā)抑郁癥中的作用

許多動(dòng)物模型和人類研究表明在應(yīng)激誘發(fā)的抑郁癥或者抑郁樣行為中,表觀遺傳修飾的變化在其中扮演著重要角色。這里從HPA軸、單胺類遞質(zhì)、BDNF三個(gè)方面介紹表觀遺傳修飾的作用。

2.1 HPA軸

HPA軸是神經(jīng)內(nèi)分泌系統(tǒng)的重要部分,參與調(diào)控應(yīng)激的反應(yīng),并調(diào)節(jié)消化、免疫、情緒、能量貯存與消耗等身體機(jī)能。應(yīng)激引起HPA軸活動(dòng)異常,HPA軸持久的活動(dòng)過度是引起抑郁癥發(fā)病的重要機(jī)制之一。而HPA軸相關(guān)基因的表觀遺傳修飾在其中發(fā)揮重要作用。

糖皮質(zhì)激素受體(glucocorticoid receptor,GR)是調(diào)節(jié) HPA軸功能的關(guān)鍵受體,與糖皮質(zhì)激素結(jié)合,通過負(fù)反饋調(diào)節(jié)機(jī)制,使HPA軸的活動(dòng)恢復(fù)正常。當(dāng)糖皮質(zhì)激素受體發(fā)生功能障礙,HPA軸負(fù)反饋機(jī)制失效。研究發(fā)現(xiàn)早期應(yīng)激引起GR的表觀遺傳修飾變化,影響HPA軸活動(dòng),從而影響抑郁癥的易感性(Farrell&O'Keane,2016)。有研究報(bào)道產(chǎn)后一周內(nèi)母鼠對(duì)子鼠照顧水平的差異,影響了子鼠成年后的糖皮質(zhì)激素受體表達(dá)及行為,這與GR的表觀遺傳修飾變化有關(guān)(Caldji et al.,1998;Weaver etal.,2004)。動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn),與獲得高水平照顧的子鼠相比,獲得低水平照顧的子鼠的海馬內(nèi)GR17啟動(dòng)子區(qū)DNA甲基化水平升高,尤其是該區(qū)域內(nèi)NGFI-A(Nervegrow th factor inducible factor)結(jié)合位點(diǎn)的DNA甲基化水平升高。高水平的DNA甲基化阻止了轉(zhuǎn)錄促進(jìn)因子NGFI-A與基因的結(jié)合,抑制了海馬GR基因的轉(zhuǎn)錄,導(dǎo)致子鼠成年后HPA軸的負(fù)反饋抑制減弱,造成HPA軸持久的活動(dòng)過度,焦慮和抑郁樣行為增多。盡管幼時(shí)獲得高水平照顧的子鼠成年后行為通常正常,但通過腦室注射L-甲硫氨酸進(jìn)行外源性干預(yù)后,幼時(shí)獲得高水平照顧的子鼠成年時(shí)會(huì)變得與低水平照顧的鼠一樣,其海馬內(nèi)GR17啟動(dòng)子區(qū)的NGFI-A結(jié)合位點(diǎn)的DNA甲基化水平升高,NGFI-A與基因的結(jié)合減少,海馬GR基因轉(zhuǎn)錄抑制,HPA軸的負(fù)反饋抑制減弱,抑郁樣行為增多(Weaver etal.,2005)。這些工作表明了HPA軸相關(guān)基因的表觀遺傳修飾在抑郁樣行為發(fā)生中的重要作用。

在人類研究中也發(fā)現(xiàn)類似的GR表觀遺傳修飾參與早期應(yīng)激引起抑郁癥發(fā)生的現(xiàn)象。童年受虐待越多越嚴(yán)重,則成年后外周血中GR啟動(dòng)子區(qū)的DNA甲基化水平越高(Perroud etal.,2011)。妊娠晚期母親的抑郁癥越嚴(yán)重,嬰兒臍帶血內(nèi)GR1F啟動(dòng)子區(qū)DNA甲基化水平越高。在產(chǎn)后三個(gè)月應(yīng)激反應(yīng)檢測(cè)中,DNA甲基化水平高的嬰兒,其HPA軸功能反應(yīng)異常(Oberlander et al.,2008)。有報(bào)道經(jīng)歷圖西族大屠殺的孕婦及其子代,其外周血中GR啟動(dòng)子區(qū)的DNA甲基化水平比同種族未有類似經(jīng)歷的健康孕婦及其子代高,GR濃度低,抑郁行為明顯(Perroud etal.,2014)。這提示GR的表觀遺傳修飾可能參與屠殺應(yīng)激引起的母子兩代抑郁癥狀的發(fā)生。

作為GR的重要分子伴侶,熱休克蛋白90(Heat shock protein 90,HSP90)也可通過調(diào)節(jié)GR的正確折疊、形成、核轉(zhuǎn)位及與靶基因的 DNA 結(jié)合,從而影響HPA 軸活動(dòng)和行為(Grad&Picard,2007)。研究發(fā)現(xiàn)小鼠中縫背核內(nèi)Hsp90的乙?；趹?yīng)激導(dǎo)致的抑郁樣行為中發(fā)揮重要作用(Jochems et al.,2015)。社會(huì)挫敗應(yīng)激使易感鼠中縫背核內(nèi)Hsp90轉(zhuǎn)錄激活性修飾乙?；浇档?GR和Hsp90相互作用增加,GR入核轉(zhuǎn)移增加,地塞米松測(cè)試和促腎上腺皮質(zhì)激素釋放因子測(cè)試時(shí),血液皮質(zhì)酮升高,產(chǎn)生社交躲避行為。而HDAC6抑制劑ACY-738的注射,使得Hsp90乙?；缴?減少了GR入核,并且逆轉(zhuǎn)了社交躲避行為。

除了GR和HSP90外,精氨酸加壓素、促腎上腺皮質(zhì)激素釋放因子及其受體等都是HPA軸活動(dòng)的重要調(diào)控因子,與抑郁癥的發(fā)生有關(guān)。研究發(fā)現(xiàn)這些基因的DNA甲基化或者H3K 9甲基化水平的改變,也在應(yīng)激引起的抑郁癥中發(fā)揮重要作用(Klengel,Pape,Binder,&Mehta,2014;van der Doelen etal.,2015;Wan etal.,2014)。

2.2 單胺類遞質(zhì)

應(yīng)激影響單胺類遞質(zhì)系統(tǒng)的釋放和更新及相關(guān)腦區(qū)的功能。其中5-羥色胺(5-hydroxytryptam in,5-HT)系統(tǒng)功能低下被認(rèn)為是抑郁癥發(fā)病的另一重要機(jī)制(Flügge,van Kampen,&M ijnster,2004)。研究發(fā)現(xiàn)應(yīng)激導(dǎo)致的表觀遺傳修飾變化在單胺類遞質(zhì)系統(tǒng)的調(diào)控中發(fā)揮重要作用。

目前研究最多的是5-羥色胺轉(zhuǎn)運(yùn)體 (5-HT transporter,5-HTT)。5-HTT是一種對(duì)5-羥色胺有高度親和力的跨膜轉(zhuǎn)運(yùn)蛋白。它能調(diào)節(jié)突觸間隙5-HT濃度,滅活腦內(nèi)5-HT神經(jīng)元釋放出的5-HT的活性,在5-羥色胺神經(jīng)傳遞中起關(guān)鍵作用,同時(shí)也是抑郁癥治療的一個(gè)重要靶點(diǎn)(Schwamborn,Brown,&Haase,2016;Zhao et al.,2015)。研究提示編碼5-HTT的基因SLC6A4(solute carrier fam ily 6 member 4)啟動(dòng)子區(qū)DNA甲基化水平的變化,參與中樞5-HT的合成和抑郁癥的發(fā)生。兒童期受虐越多,外周血中SLC6A 4啟動(dòng)子區(qū)DNA甲基化水平越高(Beach,Brody,Todorov,Gunter,&Philibert,2010;Booij etal.,2015)。外周血中SLC6A4啟動(dòng)子區(qū)DNA甲基化水平越高,外周血中SLC6A 4轉(zhuǎn)錄水平越低(Kinnally et al.,2010),額皮質(zhì)5-羥色胺合成越少(Wang et al.,2012),海馬體積越小(Booij etal.,2015)。一項(xiàng)同卵雙生子的研究表明,雙生子外周血中SLC6A 4啟動(dòng)子區(qū)DNA甲基化的差異程度與抑郁癥狀差異的程度顯著相關(guān)(Zhao,Goldberg,Bremner,&Vaccarino,2013)。恒河母猴對(duì)子猴的照顧水平越低,其子猴外周血單核細(xì)胞中SLC6A4啟動(dòng)子區(qū)DNA甲基化水平越高,成年時(shí)的身體健康指數(shù)越低(Kinnally,2014)。研究還發(fā)現(xiàn)SLC6A 4啟動(dòng)子區(qū)的DNA甲基化與S等位基因一起影響抑郁癥的易感性。攜帶S等位基因并且口腔細(xì)胞SLC6A4啟動(dòng)子區(qū)的DNA甲基化水平高的青少年易得抑郁癥(Olsson etal.,2010)。對(duì)中風(fēng)患者病后跟蹤研究發(fā)現(xiàn),SS基因型的中風(fēng)患者外周血的SLC6A4啟動(dòng)子區(qū)的DNA甲基化水平越高,抑郁癥狀越惡化(Kim,Stewart,Kang,Kim,Shin et al.,2013)。此外,抑郁癥病人外周血中SLC6A4啟動(dòng)子區(qū)所有CpG位點(diǎn)的平均DNA甲基化水平高于正常人,患者的臨床治療效果與DNA甲基化水平成負(fù)相關(guān)(Iga etal.,2016)。

多巴胺是通過其受體發(fā)揮作用的,其受體分為D1樣受體(包括D1和D5亞型)和D2樣受體(包括D2、D3和D4亞型)。D1樣受體和D2樣受體,分別與腺苷酸環(huán)化酶激活或者抑制型G蛋白偶聯(lián),從而分別升高或降低cAMP(Cyclic Adenosine monophosphate)水平,激活或抑制蛋白激酶A(protein kinase A,PKA)?？挂钟羲幬锖图?dòng)劑的研究發(fā)現(xiàn),D1樣受體和D2樣受體的激活,分別與抑郁癥的產(chǎn)生或者減弱有關(guān)(Hori&Kunugi,2013;Leggio etal.,2013)。有研究報(bào)道Par-4(Prostateapoptosis response-4)與鈣調(diào)蛋白競(jìng)爭(zhēng)D2亞型受體的結(jié)合位點(diǎn),分別促進(jìn)或阻礙D2亞型受體對(duì)cAMP、PKA的抑制作用(Moriam&Sobhani,2013)。而母愛剝奪和慢性溫和應(yīng)激引起抑郁樣行為鼠的紋狀體胞內(nèi)Ca2+水平升高。Ca2+促進(jìn)鈣調(diào)蛋白與D2亞型受體的結(jié)合,激活其下游cAMP-PKA-CREB(cAMP-responsive elementbinding protein)信號(hào)通路(Moriam&Sobhani,2013;Zhu,Peng,Zhang,&Zhang,2011)。有研究報(bào)道伏隔核內(nèi)CREB的激活與抑制分別影響鼠抑郁樣行為的產(chǎn)生或減弱(Muschamp&Carlezon,2013)。信號(hào)通路中激活的CREB是通過激活乙?；D(zhuǎn)移酶CBP(CREB-binding protein)來發(fā)揮作用的,后者使得相關(guān)基因組蛋白乙?；缴?促進(jìn)轉(zhuǎn)錄,引發(fā)鼠的抑郁樣行為(Moriam&Sobhani,2013)?？梢?應(yīng)激通過多巴胺受體介導(dǎo)的信號(hào)通路引起表觀遺傳修飾變化,參與應(yīng)激致鼠抑郁樣行為的發(fā)生。

2.3 BDNF

抑郁癥的神經(jīng)營(yíng)養(yǎng)假說認(rèn)為應(yīng)激引起腦部的BDNF水平降低會(huì)導(dǎo)致抑郁癥,而抗抑郁治療通過提高BDNF水平發(fā)揮抗抑郁作用(Duman&Monteggia,2006)。許多研究發(fā)現(xiàn)該基因的表觀遺傳修飾在其中發(fā)揮重要作用。

H3AC等組蛋白乙?；揎椇虷3K 4甲基化等組蛋白甲基化修飾與基因轉(zhuǎn)錄激活有關(guān),而H3K 9甲基化和H3K 27甲基化等組蛋白甲基化修飾與基因轉(zhuǎn)錄抑制有關(guān)。這些修飾通過調(diào)控BDNF的基因轉(zhuǎn)錄,在應(yīng)激引起抑郁癥或者抑郁樣行為中扮演重要角色。Tsankova等發(fā)現(xiàn)社會(huì)挫敗應(yīng)激使鼠海馬內(nèi)BDNFIII和IV啟動(dòng)子區(qū)轉(zhuǎn)錄抑制性修飾H3K27me2水平都升高,引起B(yǎng)DNFIII和IV表達(dá)下降,社交躲避行為增加;抗抑郁藥物丙咪嗪增強(qiáng)了鼠海馬區(qū)BDNFIII和IV啟動(dòng)子區(qū)轉(zhuǎn)錄激活性修飾H3AC水平,逆轉(zhuǎn)了應(yīng)激鼠的社交躲避行為(Tsankova etal.,2006)。研究發(fā)現(xiàn)鼠的探索活動(dòng)水平的差異可以預(yù)測(cè)抑郁易感性。根據(jù)在新異環(huán)境的探索活動(dòng)水平不同,可以把鼠分為高反應(yīng)組和低反應(yīng)組。社會(huì)挫敗應(yīng)激可以引起高反應(yīng)組快感缺失,社交躲避和體重減輕,而低反應(yīng)組沒有變化(Duclot,Hollis,Darcy,&Kabbaj,2011)。Duclot發(fā)現(xiàn)這種差異可能與BDNF表觀遺傳修飾變化不同有關(guān)(Duclot&Kabbaj,2013)。社會(huì)挫敗應(yīng)激使低反應(yīng)組BDNFVI啟動(dòng)子的兩種轉(zhuǎn)錄激活性修飾H3K 4me2和H3Ac升高、轉(zhuǎn)錄抑制性修飾H3K 9me2降低,BDNFVI轉(zhuǎn)錄激活,BDNF介導(dǎo)的信號(hào)通路激活;而高反應(yīng)組BDNFVI啟動(dòng)子區(qū)的上述三種表觀遺傳修飾不發(fā)生改變,只是H3K4me2基礎(chǔ)水平高,H3K9me2基礎(chǔ)水平低,BDNFVI轉(zhuǎn)錄不變,BDNF介導(dǎo)的信號(hào)通路并未激活。

在人類研究中,也發(fā)現(xiàn)BDNF啟動(dòng)子區(qū)的DNA甲基化參與了應(yīng)激引起的抑郁癥發(fā)生。中風(fēng)和乳腺癌患者的乳房切除手術(shù)常常對(duì)受害者的影響極大,甚至導(dǎo)致精神疾患的發(fā)生。對(duì)受害者手術(shù)后和中風(fēng)后的跟蹤研究發(fā)現(xiàn),術(shù)后和中風(fēng)后的抑郁癥患者外周血的BDNF啟動(dòng)子區(qū)的DNA甲基化水平升高,而且DNA甲基化水平越高,抑郁癥狀越惡化。這提示BDNF的DNA甲基化可能有助于腦卒中后抑郁和乳腺癌患者術(shù)后抑郁癥的檢測(cè)(Kang,Kim,Kim etal.,2015;Kim,Stewart,Kang,Kim,Kim etal.,2013)。

有學(xué)者認(rèn)為人外周血中BDNF啟動(dòng)子區(qū)DNA甲基化水平的變化,可以作為行為變化的候選靶標(biāo)。Kundakovic對(duì)子鼠的外周血、海馬區(qū)和人臍帶血的研究提示,人外周血中BDNF的DNA甲基化水平變化,可能是預(yù)測(cè)人腦內(nèi)該基因DNA甲基化水平變化、表達(dá)變化及早期應(yīng)激造成的行為變化的生物靶標(biāo)(Kundakovic etal.,2015)。人口腔組織、唾液和外周血中BDNF啟動(dòng)子區(qū)的DNA甲基化水平的變化可以作為抑郁癥診斷和老年抑郁癥診斷的候選靶標(biāo)(Fuchikam iet al.,2011;Januar,Ancelin,Ritchie,Saffery,&Ryan,2015;Kang,Kim,Bae et al.,2015;Song et al.,2014)。抑郁癥患者外周血中BDNF啟動(dòng)子區(qū)DNA甲基化水平也是自殺觀念治療效果的臨床靶標(biāo),DNA甲基化水平高的患者治療效果差(Kang etal.,2013)。

3 問題與前景

雖然抑郁癥的表觀遺傳研究取得了不少進(jìn)展,但仍處初級(jí)階段。當(dāng)前人類表觀遺傳修飾變化的許多證據(jù)主要來自于外周組織,盡管外周組織表觀遺傳修飾的變化能一定程度反映人腦組織的一些表觀遺傳修飾變化,但是二者的相關(guān)度還是有限的,并且某些表觀遺傳修飾的改變僅限于腦特定組織。由于人腦組織很難獲取,因此組建逝者腦庫以及建立特異和有效的動(dòng)物抑郁癥模型很重要。

目前有關(guān)動(dòng)物抑郁癥的造模,盡管采用應(yīng)激或者藥物引起表觀遺傳修飾的變化來觀察行為是可行的,但這種表觀遺傳修飾的變化是多基因性質(zhì)的。至今很少有特異性操縱某個(gè)單一基因的表觀遺傳修飾的研究,以驗(yàn)證該基因表觀遺傳修飾改變與相應(yīng)癥狀或行為改變的關(guān)系。近來,Heller等人(2014)通過對(duì)特定基因表觀遺傳修飾的調(diào)控,建立抑郁癥病理模型。他們利用人工鋅指蛋白(Zinc Finger Protein,ZFP)可以結(jié)合基因組特異位點(diǎn)的特性,發(fā)現(xiàn)ZFP35與組蛋白甲基轉(zhuǎn)移酶G9a形成的融合蛋白,能夠特異的提高FOSB(FBJ osteosarcoma oncogene B)啟動(dòng)子區(qū)轉(zhuǎn)錄抑制性修飾H3K9me2的水平,從而特異的抑制FOSB基因轉(zhuǎn)錄。通過病毒在鼠伏隔核大量表達(dá)G9a與ZFP35的融合蛋白時(shí),閾下應(yīng)激可以引發(fā)該鼠的社交躲避和焦慮行為;而閾下應(yīng)激沒有引起對(duì)照鼠的行為變化。未來需要更多建立特定基因表觀遺傳修飾的抑郁癥病理模型。這有望為改進(jìn)抑郁癥治療提供新方法。

另一個(gè)問題是表觀遺傳修飾酶的特異性拮抗劑的缺乏使抑郁癥的表觀遺傳研究受到一定阻礙。盡管許多研究表明DNA甲基化的改變與抑郁癥密切相關(guān),但因?yàn)镈NA甲基轉(zhuǎn)移酶特異性拮抗劑的缺乏使其在抑郁癥中分子機(jī)制的深入開展受到一定影響。目前組蛋白去乙?；?HDAC)抑制劑在抗抑郁藥物研究中受到廣泛關(guān)注。許多動(dòng)物模型實(shí)驗(yàn)表明HDAC抑制劑具有抗抑郁作用,而且促進(jìn)了其他抗抑郁藥物的效果(Fuchikam ietal.,2016)。但是HDAC抑制劑是非特異性的,可以同時(shí)抑制酶的不同亞型,因而很難確定特定的表觀遺傳修飾酶在抑郁癥中所起的作用,并且影響治療效果。在未來,研發(fā)特異性強(qiáng)的DNA甲基轉(zhuǎn)移酶拮抗劑和HDAC抑制劑,將有利于更準(zhǔn)確地進(jìn)行抑郁癥或其它精神疾病的機(jī)理研究和防治。

此外,除了DNA甲基化、組蛋白修飾的研究,應(yīng)該加強(qiáng)心理應(yīng)激方面的其他表觀遺傳機(jī)制的研究,比如非編碼RNA。同時(shí)研究也需要更多關(guān)注DNA甲基化、組蛋白修飾、非編碼RNA等相互作用共同調(diào)節(jié)基因表達(dá)的機(jī)制研究;加強(qiáng)應(yīng)激個(gè)體在不同發(fā)育過程中表觀遺傳修飾變化的研究,并從這些表觀遺傳修飾變化信息獲得疾病易感和治療的有效的時(shí)段也將是未來研究新趨勢(shì)。

4 結(jié)語

抑郁癥的表觀遺傳研究從基因與環(huán)境交互作用角度解釋應(yīng)激對(duì)人類行為的影響,為其非孟德爾遺傳特性提供研究的新視角,并成為近年來抑郁癥研究的新熱點(diǎn)。許多動(dòng)物模型和人類研究表明,在應(yīng)激誘發(fā)的抑郁癥或者抑郁樣行為中,HPA軸、單胺類遞質(zhì)、BDNF等相關(guān)基因的表觀遺傳修飾變化在其中扮演著重要角色。盡管研究還處于初級(jí)階段,但是表觀遺傳機(jī)制研究的前景廣闊,為揭示抑郁癥的發(fā)生、模擬、預(yù)測(cè)和治療將可能提供新的途徑。

Bagot,R.C.,Labonté,B.,Pe?a,C.J.,&Nestler,E.J.(2014).Epigenetic signaling in psychiatric disorders:Stress and depression.Dialogues in Clinical Neuroscience,16,281–295.

Beach,S.R.H.,Brody,G.H.,Todorov,A.A.,Gunter,T.D.,&Philibert,R.A.(2010).M ethy lation atSLC6A4is linked to fam ily history of child abuse:An exam ination of the Iow a Adoptee samp le.American Journal of Medical Genetics Part B:Neuropsychiatric Genetics,153B,710–713.

Booij,L.,Szyf,M.,Carballedo,A.,Frey,E.M.,M orris,D.,Dymov,S.,...Frodl,T.(2015).DNA methy lation of the serotonin transporter gene in peripheral cells and stressrelated changes in hippocampal volume:A study in depressed patients and healthy controls.PLoSOne,10(3),e0119061.

Cald ji,C.,Tannenbaum,B.,Sharma,S.,Francis,D.,Plotsky,P.M.,&Meaney,M.J.(1998).Maternal care during infancy regulates the development of neural system s mediating the expression of fearfulness in the rat.Proceedings of the National Academy of Sciences of the United States of America,95,5335–5340.

Delcuve,G.P.,Rastegar,M.,&Davie,J.R.(2009).Epigenetic control.Journal ofCellular Physio logy,219,243–250.

Duclot,F.,Hollis,F.,Darcy,M.J.,&Kabbaj,M.(2011).Individual differences in novelty-seeking behavior in rats as amodel for psychosocial stress-related mood disorders.Physio logy&Behavior,104,296–305.

Duclot,F.,&Kabbaj,M.(2013).Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression.The Journal ofNeuroscience,33,11048–11060.

Duman,R.S.,&Monteggia,L.M.(2006).A neurotrophic model for stress-related mood disorders.Bio logical Psychiatry,59,1116–1127.

Farrell,C.,& O'Keane,V.(2016).Epigenetics and the glucocorticoid receptor:A review of the im p lications in depression.Psychiatry Research,242,349–356.

Flügge,G.,van Kampen,M.,&M ijnster,M.J.(2004).Perturbations in brainmonoam ine system s during stress.Cell and Tissue Research,315,1–14.

Fuchikam i,M.,M orinobu,S.,Segaw a,M.,Okamoto,Y.,Yamawaki,S.,Ozaki,N.,...Terao,T.(2011).DNA methylation profiles of the brain-derived neurotrophic factor(BDNF)gene as a potent diagnostic biomarker in major depression.PLoSOne,6(8),e23881.

Fuchikam i,M.,Yamamoto,S.,Morinobu,S.,Okada,S.,Yamaw aki,Y.,&Yamaw aki,S.(2016).The potential use of histone deacetylase inhibitors in the treatment of depression.Progress in Neuro-Psychopharmaco logy and Bio logical Psychiatry,64,320–324.

Gold,P.W.(2015).The organization of the stress system and its dysregulation in depressive illness.Mo lecular Psychiatry,20,32–47.

Grad,I.,&Picard,D.(2007).The glucocorticoid responses are shaped by molecular chaperones.M olecular and Cellular Endocrinology,275(1–2),2–12.

Heller,E.A.,Cates,H.M.,Pe?a,C.J.,Sun,H.S.,Shao,N.Y.,Feng,J.,...Nestler,E.J.(2014).Locus-specific epigenetic remodeling controls addiction-and depression-related behaviors.Nature Neuroscience,17,1720–1727.

Hori,H.,&Kunugi,H.(2013).Dopam ine agonist-responsive depression.Psychogeriatrics,13,189–195.

Iga,J.I.,Watanabe,S.Y.,Numata,S.,Umehara,H.,Nishi,A.,Kinoshita,M.,...Ohmori,T.(2016).Association study of polymorphism in the serotonin transporter gene promoter,methy lation profiles,and expression in patients w ith major depressive disorder.Human Psychopharmacology:Clinical and Experimental,31,193–199.

Januar,V.,Ancelin,M.L.,Ritchie,K.,Saffery,R.,&Ryan,J.(2015).BDNF promotermethylation and genetic variation in late-life depression.Translational Psychiatry,5(8),e619.

Jochem s,J.,Teegarden,S.L.,Chen,Y.,Boulden,J.,Challis,C.,Ben-Dor,G.A.,...Berton,O.(2015).Enhancement of stress resilience through histone deacety lase 6-mediated regulation of glucocorticoid receptor chaperone dynam ics.Bio logical Psychiatry,77,345–355.

Kang,H.J.,K im,J.M.,Bae,K.Y.,Kim,S.W.,Shin,I.S.,Kim,H.R.,...Yoon,J.S.(2015).Longitudinal associations betweenBDNFpromotermethylation and late-life depression.Neurobio logy ofAging,36,1764.e1–1764.e7.

Kang,H.J.,Kim,J.M.,Kim,S.Y.,K im,S.W.,Shin,I.S.,Kim,H.R.,...Yoon,J.S.(2015).A longitudinal study ofBDNFpromoter methylation and depression in breast cancer.Psychiatry Investigation,12,523–531.

Kang,H.J.,K im,J.M.,Lee,J.Y.,K im,S.Y.,Bae,K.Y.,Kim,S.W.,...Yoon,J.S.(2013).BDNF promotermethylation and suicidal behavior in depressive patients.Journal of Affective Disorders,151,679–685.

K im,J.M.,Stewart,R.,Kang,H.J.,Kim,S.Y.,K im,S.W.,Shin,I.S.,...Yoon,J.S.(2013).A longitudinal study ofBDNFpromotermethy lation and genotype w ith poststroke depression.Journal ofAffective Disorders,149(1–3),93–99.

K im,J.M.,Stewart,R.,Kang,H.J.,Kim,S.W.,Shin,I.S.,Kim,H.R.,...Yoon,J.S.(2013).A longitudinal study ofSLC6A4DNA promoter methy lation and poststroke depression.Journal ofPsychiatric Research,47,1222–1227.

K innally,E.L.(2014).Epigenetic plasticity follow ing early stress predicts long-term health outcomes in rhesusmacaques.American Journal ofPhysical Anthropology,155,192–199.

K innally,E.L.,Capitanio,J.P.,Leibel,R.,Deng,L.,LeDuc,C.,Haghighi,F.,&Mann,J.J.(2010).Epigenetic regulation of serotonin transporter expression and behavior in infant rhesusmacaques.Genes,Brain and Behavior,9,575–582.

K lengel,T.,Pape,J.,Binder,E.B.,&Mehta,D.(2014).The role of DNA methy lation in stress-related psychiatric disorders.Neuropharmaco logy,80,115–132.

K rishnan,V.,&Nestler,E.J.(2011).Animal models of depression:M olecular perspectives.In J.J.Hagan(Ed),Mo lecular andfunctional models inneuropsychiatry:Current topics in behavioral neurosciences(vol.7,pp.121–147).Berlin Heidelberg,Germany:Springer.

Kundakovic,M.,Gudsnuk,K.,Herbstman,J.B.,Tang,D.L.,Perera,F.P.,&Champagne,F.A.(2015).DNA methylation of BDNF as a biomarker of early-life adversity.Proceedings of the National Academy of Sciences of the United States ofAmerica,112,6807–6813.

Leggio,G.M.,Salomone,S.,Bucolo,C.,Platania,C.,M icale,V.,Caraci,F.,&Drago,F.(2013).Dopam ine D3receptor as a new pharmacological target for the treatment of depression.EuropeanJournalofPharmaco logy,719(1–3),25–33.

Lockw ood,L.E.,Su,S.Y.,&Youssef,N.A.(2015).The role of epigenetics in depression and suicide:A platform for gene-environment interactions.Psychiatry Research,228,235–242.

Lopizzo,N.,Chiavetto,L.B.,Cattane,N.,Plazzotta,G.,Tarazi,F.I.,Pariante,C.M.,…Cattaneo,A.(2014).Gene-environment interaction in major depression:Focus on experience-dependent biological system s.Frontiers in Psychiatry,6,68.

Mathers,C.D.,&Loncar,D.(2006).Projections of global mortality and burden of disease from 2002 to 2030.PLoS Medicine,3(11),e442.

Menke,A.,K lengel,T.,&Binder,E.B.(2012).Epigenetics,depression and antidepressant treatment.Current Pharmaceutical Design,18,5879–5889.

Moriam,S.,&Sobhani,M.E.(2013).Epigenetic effect of chronic stress on dopam ine signaling and depression.Genetics&Epigenetics,5,11–16.

Muscham p,J.W.,&Carlezon,W.A.,Jr.(2013).Roles of nucleus accumbens CREB and dynorphin in dysregulation of motivation.Co ldSpringHarborPerspectivesin Medicine,3(2),a012005.

Oberlander,T.F.,Weinberg,J.,Papsdorf,M.,Grunau,R.,M isri,S.,&Dev lin,A.M.(2008).Prenatal exposure to maternal depression,neonatal methy lation of human glucocorticoid receptor gene(NR3C1)and infant cortisol stress responses.Epigenetics,3,97–106.

Olsson,C.A.,Foley,D.L.,Parkinson-Bates,M.,Byrnes,G.,M cKenzie,M.,Patton,G.C.,...Saffery,R.(2010).Prospects for epigenetic research w ithin cohort studies of psychological disorder:A pilot investigation of a peripheral cell marker of epigenetic risk for depression.Bio logical Psycho logy,83,159–165.

Pechtel,P.,&Pizzagalli,D.A.(2011).Effects of early life stress on cognitive and affective function:An integrated review ofhuman literature.Psychopharmacology,214,55–70.

Perroud,N.,Paoloni-Giacobino,A.,Prada,P.,Olié,E.,Salzmann,A.,Nicastro,R.,...Malafosse,A.(2011).Increased methylation of glucocorticoid receptor gene(NR3C1)in adults w ith a history of childhood maltreatment:A link w ith the severity and type of trauma.Translational Psychiatry,1(12),e59.

Perroud,N.,Rutembesa,E.,Paoloni-Giacobino,A.,Mutabaruka,J.,M utesa,L.,Stenz,L.,...Karege,F.(2014).The Tutsi genocide and transgenerational transm ission of maternal stress:Epigenetics and biology of the HPA axis.The World Journal ofBio logical Psychiatry,15,334–345.

Schw amborn,R.,Brow n,E.,&Haase,J.(2016).Elevation of cortical serotonin transporter activity upon peripheral immune challenge is regulated independently of p38 m itogen-activated protein kinase activation and transporter phosphorylation.Journal ofNeurochemistry,137,423–435.

Song,Y.X.,M iyaki,K.,Suzuki,T.,Sasaki,Y.,Tsutsum i,A.,Kaw akam i,N.,...Shimbo,T.(2014).A ltered DNA methylation status of human brain derived neurotrophis factor gene could be useful as biomarker of depression.American Journal ofMedical Genetics Part B:Neuropsychiatric Genetics,165,357–364.

Tsankova,N.M.,Berton,O.,Renthal,W.,Kumar,A.,Neve,R.L.,&Nestler,E.J.(2006).Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.Nature Neuroscience,9,519–525.

van der Doelen,R.H.A.,Arnoldussen,I.A.,Ghareh,H.,van Och,L.,Homberg,J.R.,&Kozicz,T.(2015).Early life adversity and serotonin transporter gene variation interact to affect DNA methy lation of the corticotropin-releasing factor gene promoter region in the adult rat brain.Development and Psychopatho logy,27,123–135.

Wan,Q.R.,Gao,K.,Rong,H.,Wu,M.,Wang,H.L.,Wang,X.P.,...Liu,Z.C.(2014).Histone modifications of theCrhr1gene in a ratmodel of depression follow ing chronic stress.Behavioural Brain Research,271,1–6.

Wang,D.S.,Szy f,M.,Benkelfat,C.,Proven?al,N.,Turecki,G.,Caramaschi,D.,...Booij,L.(2012).PeripheralSLC6A4DNA methylation is associated w ithin vivomeasures of human brain serotonin synthesis and childhood physical aggression.PLoSOne,7(6),e39501.

Weaver,I.C.G.,Cervoni,N.,Champagne,F.A.,D'A lessio,A.C.,Sharma,S.,Seckl,J.R.,...M eaney,M.J.(2004).Epigenetic programm ing by maternal behavior.Nature Neuroscience,7,847–854.

Weaver,I.C.G.,Cham pagne,F.A.,Brow n,S.E.,Dymov,S.,Sharma,S.,M eaney,M.J.,&Szyf,M.(2005).Reversal of maternal programm ing of stress responses in adult offspring through methy l supplementation: A ltering epigeneticmarking later in life.The Journal ofNeuroscience,25,11045–11054.

Zhao,J.Y.,Goldberg,J.,Bremner,J.D.,&Vaccarino,V.(2013).Association between promoter methylation of serotonin transporter gene and depressive sym ptom s:A monozygotic tw in study.Psychosomatic Medicine,75,523–529.

Zhao,R.,Wang,S.B.,Huang,Z.L.,Zhang,L.,Yang,X.Y.,Bai,X.Y.,...Du,G.H.(2015).Lipopolysaccharidexinduced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A 3 adenosine receptor.Bioscience Trends,9,367–376.

Zhu,X.Z.,Peng,S.F.,Zhang,S.,&Zhang,X.W.(2011).Stress-induced depressive behaviors are correlated w ith Par-4 and DRD 2 expression in rat striatum.Behavioural Brain Research,223,329–335.