陳祥和 李文秀 劉 波 殷榮賓

骨源性因子ucOCN在運(yùn)動(dòng)抗抑郁中的作用機(jī)制*

陳祥和1李文秀1劉 波1殷榮賓2

(1揚(yáng)州大學(xué)體育學(xué)院, 江蘇 揚(yáng)州 225127) (2蘇州大學(xué)體育學(xué)院, 江蘇 蘇州 215000)

羧化不全骨鈣素(ucOCN)是骨中成骨細(xì)胞分泌的特異性蛋白, 因其在調(diào)控神經(jīng)發(fā)育、神經(jīng)可塑性等中的重要角色而受到神經(jīng)科學(xué)領(lǐng)域關(guān)注?！肮?腦”串聯(lián)“對話”是骨內(nèi)分泌?神經(jīng)介導(dǎo)的應(yīng)答系統(tǒng), ucOCN透過血腦屏障后介導(dǎo)單胺類神經(jīng)遞質(zhì)、神經(jīng)內(nèi)分泌、神經(jīng)免疫、神經(jīng)再生及基因表達(dá)等機(jī)制, 進(jìn)而作用于海馬CA3區(qū)、扣帶回等腦區(qū)功能發(fā)揮來調(diào)節(jié)抑郁發(fā)生及改善。而ucOCN作為骨源性力學(xué)刺激敏感基因, 運(yùn)動(dòng)上調(diào)其表達(dá)后進(jìn)入血液循環(huán), 通過介導(dǎo)5-HT/GABA分泌、HPA軸功能、炎癥反應(yīng)、神經(jīng)營養(yǎng)因子(BDNF等)表達(dá)或信號途徑(如GSK3β/β-catenin、TLR4/miR-223/NLRP3等)激活等來實(shí)現(xiàn)“骨串聯(lián)腦”, 發(fā)揮運(yùn)動(dòng)抗抑郁作用。通過對骨源性因子ucOCN介導(dǎo)腦區(qū)功能變化從而實(shí)現(xiàn)運(yùn)動(dòng)抗抑郁的作用機(jī)制進(jìn)行探討、梳理, 一方面有助于更深入了解骨內(nèi)分泌功能, 另一方面為抑郁發(fā)生、改善和運(yùn)動(dòng)抗抑郁研究提供新的理論基礎(chǔ)和研究思路。

羧化不全骨鈣素, 骨, 腦, 運(yùn)動(dòng), 抑郁癥

抑郁癥不僅是社會重大焦點(diǎn)問題, 其發(fā)病機(jī)制探究亦是神經(jīng)科學(xué)領(lǐng)域的研究熱點(diǎn)。研究發(fā)現(xiàn), 單胺類神經(jīng)遞質(zhì)分泌、下丘腦?垂體?腎上腺軸(Hypothalamic–pituitary–adrenal axis, HPA)、細(xì)胞因子表達(dá)等功能的失調(diào), 可通過作用于眶皮質(zhì)區(qū)、海馬扣帶回及下丘腦等腦內(nèi)結(jié)構(gòu), 調(diào)控中縫核及其軸突路徑相關(guān)結(jié)構(gòu)內(nèi)神經(jīng)元中神經(jīng)遞質(zhì)如5-羥色胺(5-hydroxytryptamine, 5-HT)）分泌、關(guān)鍵因子表達(dá)等, 進(jìn)而影響抑郁的發(fā)生、發(fā)展?，F(xiàn)已證實(shí)的抑郁癥發(fā)病機(jī)制主要有：單胺類神經(jīng)遞質(zhì)假說、基因?環(huán)境相互作用、神經(jīng)發(fā)生、神經(jīng)可塑性、免疫激活與抑制等(Frye & Walf, 2009)。骨鈣素(Osteocalcin, OCN)作為骨中成骨細(xì)胞(Osteoblast, OB)分泌的特異性非膠原蛋白(Lin et al., 2020), 其活化形式羧化不全骨鈣素(Uncarboxylated osteocalcin, ucOCN)經(jīng)生物信號刺激后, 由骨分泌入血后作用于胰島β細(xì)胞、睪丸、脂肪、腦等組織器官, 通過靶細(xì)胞膜受體引起級聯(lián)反應(yīng)調(diào)控能量代謝、精子形成、認(rèn)知功能障礙等(Vella & Kumar, 2013)。

OB具有內(nèi)分泌功能, 將OB上的ucOCN基因敲除后, ucOCN-/-小鼠記憶力和空間學(xué)習(xí)能力下降且出現(xiàn)抑郁樣行為; 而注射外源性ucOCN后, ucOCN-/-小鼠抑郁樣行為顯著改善(Khrimian et al., 2017)。提示, OB分泌的特異性ucOCN在抑郁發(fā)生上具有“骨?腦Crosstalk”調(diào)控作用。運(yùn)動(dòng)是改善抑郁的有效手段, 但相關(guān)研究焦點(diǎn)集中于中樞神經(jīng)系統(tǒng)可塑性適應(yīng)變化上。近來發(fā)現(xiàn), OB中的ucOCN作為運(yùn)動(dòng)敏感基因, 其活化入血穿過血腦屏障后與G蛋白偶聯(lián)受體158 (G protein-coupled receptors 158, Gpr158)結(jié)合調(diào)節(jié)靶基因腦源性神經(jīng)營養(yǎng)因子(Brain-derived neurotrophic factor, BDNF)表達(dá), 調(diào)控抑郁發(fā)生、改善(Khrimian et al., 2017)。國內(nèi)劉微娜團(tuán)隊(duì)在探究運(yùn)動(dòng)抗抑郁時(shí)提出了：“腦?腸互動(dòng)”、“肌?腦Crosstalk”、脂肪細(xì)胞因子等理論(薛香莉等, 2019) (夏杰等, 2017) (劉文彬等, 2018)。但基于整合生物學(xué)理論和骨內(nèi)分泌功能, 本論文將著重探究ucOCN介導(dǎo)“骨?腦Crosstalk”發(fā)揮運(yùn)動(dòng)抗抑郁的生物學(xué)效應(yīng)和可能機(jī)制, 進(jìn)而深層次揭示骨內(nèi)分泌活動(dòng)與運(yùn)動(dòng)抗抑郁的分子關(guān)系, 為運(yùn)動(dòng)健腦提供思路和理論依據(jù)。

1 ucOCN介導(dǎo)“骨?腦Crosstalk”在抑郁發(fā)生中的作用機(jī)制

1.1 ucOCN調(diào)節(jié)多巴胺、γ-氨基丁酸等神經(jīng)遞質(zhì)

5-HT、多巴胺(Dopamine, DA)、γ-氨基丁酸(γ-aminobutyric acid, GABA)等單胺類神經(jīng)遞質(zhì)快速再攝取和抑制降解改善腦區(qū)突觸間隙信息傳遞, 調(diào)控抑郁發(fā)生及其遺傳易感性(Andolina et al., 2014)。5-HT濃度快速升高后, 與5-HT1B受體相互作用的鈣結(jié)合蛋白p11在海馬扣帶回中表達(dá)下調(diào),而5-HT特異性再攝取抑制劑——SSRIs干預(yù)后, 其在海馬扣帶回表達(dá)上調(diào), 介導(dǎo)抗抑郁(Wolf et al., 2018)。SSRIs還可抑制5-HT轉(zhuǎn)運(yùn)體(5-Hydroxytamine transporter, SERT)表達(dá)及功能, 提高突觸間隙5-HT水平來發(fā)揮抗抑郁作用(Baudry et al., 2010)。隨著研究深入, 除經(jīng)典5-HT外, 學(xué)者們開始關(guān)注谷氨酸能和DA能遞質(zhì)系統(tǒng)在抑郁發(fā)生中的作用。臨床研究證實(shí), 抗抑郁藥物可降低抑郁癥患者血清中升高的谷氨酸(Zhang et al., 2013)。而動(dòng)物研究發(fā)現(xiàn), 抑郁小鼠海馬釋放的谷氨酸顯著增加(Ding et al., 2017)。氯胺酮作為非競爭性N-甲基-D-天冬氨酸受體(N-Methyl-D-aspartic receptor, NMDAR)拮抗劑, 對頑固型抑郁癥患者靜脈注射亞麻醉劑量氯胺酮后可在2 h內(nèi)快速產(chǎn)生抗抑郁作用(Zanos et al., 2019)。提示, 腦谷氨酸能遞質(zhì)系統(tǒng)調(diào)控抑郁發(fā)生。進(jìn)一步研究發(fā)現(xiàn), 其分子機(jī)制與以下兩方面有關(guān)：谷氨酸激活哺乳動(dòng)物雷帕霉素靶蛋白(Mammalian target of rapamycin, mTOR)途徑增加前額葉皮層神經(jīng)元的突觸數(shù)量; 氯胺酮下調(diào)沉默狀態(tài)NMDAR表達(dá)后抑制真核起始因子2 (Eukaryotic initiation factor 2, eEF2)激酶(CaMKIII)活性, 導(dǎo)致eEF2去磷酸化并促進(jìn)皮層BDNF翻譯(Gu et al., 2017)。DA調(diào)控慢性應(yīng)激導(dǎo)致的大鼠抑郁樣行為, 其機(jī)制與DA能神經(jīng)元突觸傳遞被抑制, 且右側(cè)下額葉、紋狀體、海馬齒狀回等腦區(qū)DA濃度顯著降低密切相關(guān); 而DA受體激動(dòng)劑則能改善應(yīng)激型大鼠的抑郁樣行為(Kowiański et al., 2018)。最近研究顯示, 人腦組織中多巴胺D1和D2受體結(jié)合增多, 而干預(yù)抑郁樣小鼠腦區(qū)兩受體結(jié)合則產(chǎn)生顯著抗抑郁效應(yīng)(Zhao, Ying, et al., 2019)。單胺類神經(jīng)遞質(zhì)在介導(dǎo)抑郁和運(yùn)動(dòng)抗抑郁中的作用已被證實(shí), 而隨著研究深入, 有學(xué)者對此假說提出異議。但是, 不可否認(rèn)的是單胺類神經(jīng)遞質(zhì)調(diào)控抑郁發(fā)生和抗抑郁中的作用可能與其他神經(jīng)生物學(xué)機(jī)制存在密切關(guān)系。

OCN經(jīng)OB分泌后穿過血腦屏障, 在海馬和中腦中與神經(jīng)元相結(jié)合, 促進(jìn)單胺類神經(jīng)遞質(zhì)合成的同時(shí)抑制GABA合成, 進(jìn)而改善抑郁; 且懷孕期間向OCN-/-母體小鼠注射OCN可有效預(yù)防OCN-/-后代小鼠的抑郁表征出現(xiàn)(Oury et al., 2013)。后續(xù)研究發(fā)現(xiàn), OCN發(fā)揮作用是以ucOCN的形式調(diào)控大腦發(fā)育和腦功能, 其缺失導(dǎo)致空間學(xué)習(xí)能力和記憶力嚴(yán)重缺陷, 加劇抑郁樣行為(Rentz et al., 2020)。磁共振掃描發(fā)現(xiàn), ucOCN-/-小鼠大腦比其同窩WT小鼠小, 海馬裂和海馬傘之間的齒狀回CA4區(qū)覆蓋區(qū)域減少30%, 并且海馬體半球間胼胝體消失(Shan et al., 2019)。而ucOCN抑制GABA合成, 導(dǎo)致腦和腦干中DA和NE降低20%～50%; OB上特異性敲除ucOCN后, ucOCN–/–小鼠空間學(xué)習(xí)和記憶能力顯著下降, 且出現(xiàn)焦慮和抑郁樣行為。注射外源性ucOCN后, 其穿過血腦屏障并與中腦腹側(cè)A11細(xì)胞群、海馬顳橫回和腦干中神經(jīng)元結(jié)合, 促進(jìn)神經(jīng)遞質(zhì)合成、分泌并抑制GABA合成, 從而促進(jìn)學(xué)習(xí)和記憶能力及抗焦慮、抑郁作用(Liu et al., 2018)。在探究氯胺酮抗抑郁時(shí), 發(fā)現(xiàn)ucOCN表達(dá)上調(diào)能增加前額葉皮質(zhì)(Prefrontal cortex, PFC)突觸神經(jīng)小體中突觸前蛋白SynapsinⅠ及突觸后致密蛋白95 (Postsynaptic density protein 95, PSD95)和谷氨酸受體1 (Glutamate receptor 1, GLuR1)表達(dá), 改善抑郁樣行為; 靶向性注射ucOCN siRNA可降低SynapsinⅠ等突觸蛋白表達(dá), 抑制氯胺酮的抗抑郁作用(aan het Rot et al., 2010)?？旄腥笔ё鳛橐钟舭Y典型癥狀, 是大腦獎(jiǎng)賞系統(tǒng)功能障礙的直接體現(xiàn), 其大腦的中腦腹側(cè)被蓋區(qū)(Ventral tegmental area, VTA)內(nèi)DA能神經(jīng)的放電頻率明顯增加, ucOCN穿過血腦屏障進(jìn)入VTA后降低DA能神經(jīng)元放電頻率, 通過“骨?腦Crosstalk”來改善抑郁表征(Krishnan et al., 2007)。

ucOCN可通過調(diào)節(jié)神經(jīng)遞質(zhì)基因表達(dá)來改善抑郁。如ucOCN下調(diào)NMDA后促進(jìn)谷氨酸受體AMPAR表達(dá), 抑制CaMKIII活性, 導(dǎo)致eEF2去磷酸化并上調(diào)皮層中BDNF表達(dá), 促進(jìn)谷氨酸產(chǎn)生, 減少抑制性神經(jīng)遞質(zhì)GABA表達(dá), 發(fā)揮“骨?腦Crosstalk”快速抗抑郁作用(周嬋娟, 2016)。后續(xù)研究發(fā)現(xiàn), 骨源性ucOCN通過血液途徑穿過血腦屏障后與海馬CA3區(qū)神經(jīng)元膜上Gpr158結(jié)合, 作用于長鏈非編碼RNA漿細(xì)胞瘤變體易位基因1 (Long-chain non-coding RNA plasmacytic variant transposable gene 1, PVT1)表達(dá)來實(shí)現(xiàn)“骨?腦Crosstalk”調(diào)控抑郁, 當(dāng)Gpr158活化后可激活I(lǐng)P3Rs和靶基因BDNF表達(dá), 進(jìn)而促進(jìn)神經(jīng)遞質(zhì)表達(dá), 改善抑郁(Khrimian et al., 2017)。慢性應(yīng)激壓力亦可導(dǎo)致前額葉皮層(Prefrontal cortex, PFC)中Gpr158表達(dá)上調(diào), 通過調(diào)節(jié)改變AMPA受體活性的突觸強(qiáng)度來誘導(dǎo)抑郁樣行為(Sutton et al., 2018)。在此通路中, Gpr158被證實(shí)是ucOCN的腦神經(jīng)元靶受體, 且ucOCN和Gpr158在調(diào)控抑郁發(fā)生中的作用關(guān)系已被發(fā)現(xiàn)和證實(shí)。

1.2 ucOCN調(diào)節(jié)神經(jīng)內(nèi)分泌

神經(jīng)內(nèi)分泌是調(diào)控抑郁癥發(fā)生的主因之一。研究顯示, 抑郁癥小鼠血清糖皮質(zhì)激素(Glucocorticoid, GC)和促腎上腺皮質(zhì)激素釋放激素(Corticotropin releasing hormone, CRH)均顯著升高, 且正常小鼠長期注射GC和/或CRH均會出現(xiàn)抑郁樣行為(Edvinsson et al., 2020)。基于此, 學(xué)者們開始關(guān)注HPA軸在抑郁發(fā)生中的作用。該軸在長期慢性應(yīng)激下會反復(fù)持續(xù)被激活, 導(dǎo)致GC、促腎上腺皮質(zhì)激素(Adrenocorticotropic hormone, ACTH)和皮質(zhì)醇等分泌異常, 而過量GC、ACTH等通過激活其受體可抑制小鼠海馬齒狀回顆粒下區(qū)(Subgranular zone, SGZ)神經(jīng)干細(xì)胞的增殖并導(dǎo)致海馬萎縮(Rubin et al., 1987)。這也揭示了抑郁癥患者腦內(nèi)海馬組織體積萎縮的機(jī)制。并且, HPA軸異常導(dǎo)致腦神經(jīng)元細(xì)胞喪失、樹突萎縮、可塑性受損, 降低海馬對HPA軸的負(fù)反饋調(diào)節(jié)(Eyre & Baune, 2012)。在探究胰島素與抑郁的發(fā)生關(guān)系時(shí), 發(fā)現(xiàn)胰島素敏感性改變激活免疫炎癥網(wǎng)絡(luò), 損傷神經(jīng)元或神經(jīng)膠質(zhì)細(xì)胞, 降低大腦皮質(zhì)興奮(Mcintyre et al., 2007); 胰島素抑制大腦NE再攝取, 逆向抑制下丘腦兒茶酚胺和海馬中磷酸肌醇表達(dá), 抑制NE和DA轉(zhuǎn)運(yùn)蛋白, 鋰鹽代謝失衡, 導(dǎo)致抑郁發(fā)生(周嬋娟, 2016; Gould & Manji, 2005)。

骨中ucOCN通過血液循環(huán)作用于腎上腺皮質(zhì)束狀帶細(xì)胞內(nèi)質(zhì)網(wǎng), 導(dǎo)致小鼠血清GC濃度降低, 而敲除ucOCN后GC長期處于較高水平并引發(fā)抑郁表現(xiàn)(Mar et al., 2020)。另一研究中, 抑郁癥患者血清ucOCN濃度升高的同時(shí)伴隨GC分泌異常(Eyre & Baune, 2012)。ucOCN抑制GC合成、分泌, 進(jìn)而抑制前額葉皮層和海馬區(qū)核轉(zhuǎn)錄因子- κB (Nuclear factor kappa-B, NF-κB)途徑, 小鼠抑郁樣行為被改善(Edvinsson et al., 2020)。并且, 在探究ucOCN調(diào)控抑郁發(fā)生機(jī)制時(shí), 發(fā)現(xiàn)抑郁癥患者血清ucOCN表達(dá)下調(diào)激活HPA軸, 導(dǎo)致ACTH和皮質(zhì)醇濃度異常升高(Rubin et al., 1987)。而GC、ACTH和皮質(zhì)醇分泌異常導(dǎo)致腦部神經(jīng)元受損、可塑性下降, 抑制海馬對HPA軸的負(fù)反饋調(diào)節(jié)(Eyre & Baune, 2012)。GPRC6A是ucOCN在腦內(nèi)海馬、扣帶回、齒狀回等和胰腺b細(xì)胞中的靶受體, 敲除ucOCN后, GPRC6A失活會抑制小鼠胰島素分泌產(chǎn)生(de Toni et al., 2019); 臨床研究亦發(fā)現(xiàn), 2型糖尿病(Type 2 diabetes mellitus, T2DM)患者血清ucOCN與胰島素分泌呈顯著正相關(guān)(Liang et al., 2016)。T2DM小鼠血清ucOCN下降導(dǎo)致抑郁樣行為出現(xiàn), 而外源性ucOCN可顯著改善ucOCN-/-小鼠的抑郁行為。其分子機(jī)制與胰島素分泌減少激活海馬炎癥反應(yīng)和提高IR水平, 導(dǎo)致Ca2+通道被抑制并下調(diào)膜蛋白Ezrin表達(dá), 引起小膠質(zhì)細(xì)胞、星型膠質(zhì)細(xì)胞等功能失常和神經(jīng)元細(xì)胞受損、死亡有關(guān)(牛望等, 2020)。綜上所述, 抑郁發(fā)生與骨源性ucOCN介導(dǎo)的胰島素信號途徑密切相關(guān), 并且這在一定程度上也揭示了T2DM共病抑郁癥發(fā)生的分子機(jī)制。

1.3 ucOCN介導(dǎo)神經(jīng)免疫機(jī)制

抑郁發(fā)生與壓力應(yīng)激和T淋巴細(xì)胞、B淋巴細(xì)胞、自然殺傷細(xì)胞(Natural killer cell, NK)等免疫細(xì)胞數(shù)量和活性降低, 促炎因子[腫瘤壞死因子- α (Tumor necrosis factor-α, TNF-α)、白介素6 (Interleukin-6, IL-6)等]釋放等多種免疫功能異常密切相關(guān)。應(yīng)激狀態(tài)下, CRH增加、交感神經(jīng)系統(tǒng)和HPA軸激活引起皮質(zhì)醇等激素釋放, 抑制正常免疫反應(yīng)(胡亮等, 2019)。近幾年, 神經(jīng)免疫在抑郁發(fā)生中的作用機(jī)制受到重點(diǎn)關(guān)注。研究表明, 神經(jīng)炎癥通過調(diào)控神經(jīng)再生、HPA軸功能等來影響抑郁和抑郁樣神經(jīng)病變發(fā)生。IL-10作為抗炎因子, 其介導(dǎo)抑郁發(fā)生, 當(dāng)對抑郁大鼠注射IL-10后可顯著改善其神經(jīng)功能; 同時(shí), 海馬中IL-1β和TNF-α表達(dá)下調(diào), 實(shí)質(zhì)中積聚的中性粒細(xì)胞數(shù)量減少, 神經(jīng)保護(hù)增強(qiáng)(Knoblach & Faden, 1998)。人體研究發(fā)現(xiàn), 抑郁發(fā)生后T細(xì)胞募集, 通過對抑郁癥患者腦組織分析, 發(fā)現(xiàn)海馬區(qū)CD3+、CD4+T淋巴細(xì)胞高表達(dá), 而75%樣本中存在CD8+T淋巴細(xì)胞高表達(dá)(Holmin et al., 1998)。但該研究樣本數(shù)量僅9例, 結(jié)果存在一定局限性。有研究卻發(fā)現(xiàn), 少突膠質(zhì)細(xì)胞、小膠質(zhì)細(xì)胞和星型膠質(zhì)細(xì)胞等在神經(jīng)系統(tǒng)中均可形成補(bǔ)體, 抑郁發(fā)生后募集活化的T淋巴細(xì)胞、巨噬細(xì)胞和中性粒細(xì)胞等來合成和分泌補(bǔ)體蛋白(Woodruff et al., 2010; Hansen & Malcangio, 2013)。小膠質(zhì)細(xì)胞激活補(bǔ)體受體3 (Complement receptor 3, CR3)在抑郁神經(jīng)系統(tǒng)病變中發(fā)揮突觸修剪作用(Kettenmann et al., 2013)。小膠質(zhì)細(xì)胞激活CR3后引起海馬長時(shí)程突觸抑制, 在神經(jīng)炎癥導(dǎo)致抑郁等相關(guān)腦功能障礙中導(dǎo)致突觸損壞及記憶損傷(Zhang et al., 2014)。LIAN等發(fā)現(xiàn), 神經(jīng)炎癥因子NF-κB激活星型膠質(zhì)細(xì)胞補(bǔ)體C3來參與抑郁發(fā)生(Lian et al., 2015)。并且, NF-κB激活后促進(jìn)小膠質(zhì)細(xì)胞釋放C3, 并作用于神經(jīng)細(xì)胞上C3受體引起突觸功能改變; 此外, NF-κB/C3/C3aR途徑還參與神經(jīng)細(xì)胞內(nèi)鈣電流調(diào)節(jié), 增強(qiáng)興奮狀態(tài)下突觸后電流。然而, 突觸后電流受AMPAR調(diào)節(jié), 介導(dǎo)抑郁的突觸重塑(丘玥等, 2016)。表明, 神經(jīng)系統(tǒng)自身合成補(bǔ)體參與抑郁的發(fā)生、發(fā)展。抑郁發(fā)生還與IL-1等細(xì)胞因子透過血腦屏障刺激脈絡(luò)叢和第四腦室周圍丘腦、下丘腦、海馬、室旁核等器官組織中白細(xì)胞增多, 進(jìn)而引起的免疫反應(yīng)有關(guān)。

mTOR是調(diào)節(jié)免疫反應(yīng)的關(guān)鍵因子, 可通過調(diào)控APP剪切酶如：淀粉蛋白前β位分解酶1 (β-site APP-cleaving enzyme l, BACE1)、Disintegrin和金屬蛋白酶結(jié)構(gòu)域15 (Metalloproteinase domain 15, ADAM15)表達(dá)來維持海馬突觸可塑性和記憶形成的關(guān)鍵因子, 而阻斷ucOCN介導(dǎo)的絲氨酸/蘇氨酸激酶(Serine/threonine kinase, AKT)/mTOR/ NF-κB途徑后, ucOCN調(diào)控抑郁發(fā)生的作用消失(Stepanichev et al., 2014)。星型膠質(zhì)細(xì)胞是一種神經(jīng)元功能輔助細(xì)胞, 參與炎癥反應(yīng), 抑郁發(fā)生后星型膠質(zhì)細(xì)胞數(shù)量和密度減少、形態(tài)萎縮(Halassa et al., 2009; Jun et al., 2014)。在探究不同濃度ucOCN對C57BL/6乳鼠星型膠質(zhì)細(xì)胞增殖影響時(shí),發(fā)現(xiàn)相較于其它濃度, 30 ng/mL ucOCN可顯著上調(diào)CyclinD2、D3、E及B1表達(dá), 促進(jìn)G1和G1/S期星型膠質(zhì)細(xì)胞增殖(王新發(fā), 2017)。然而, ucOCN功能缺失導(dǎo)致星型膠質(zhì)細(xì)胞能量代謝紊亂,三磷酸腺苷(Adenosine triphosphate, ATP)不能正常合成, 缺乏肌醇1, 4, 5-三磷酸受體2型(Inositol 1, 4, 5-trisphosphate receptors 2, IP3Rs2)和轉(zhuǎn)基因阻滯的囊泡膠質(zhì)細(xì)胞誘導(dǎo)星型膠質(zhì)細(xì)胞ATP釋放缺陷, 而補(bǔ)充ATP可刺激星型膠質(zhì)細(xì)胞的內(nèi)源性ATP釋放在小鼠抑郁癥模型中誘導(dǎo)抗抑郁樣效應(yīng), 進(jìn)而在內(nèi)側(cè)PFC中的三磷酸腺苷受體(Adenosine Triphosphate Receptor, P2X2)受體介導(dǎo)ATP的抗抑郁樣作用(Liu et al., 2004)。并且, 星型膠質(zhì)細(xì)胞通過局部K+攝取和空間K+緩沖星型膠質(zhì)細(xì)胞阻止細(xì)胞外K+的積累以及興奮性氨基酸轉(zhuǎn)運(yùn)蛋白1 (Excitatory amino acid transporter 1, EAAT1)、EAAT2 Na+依賴轉(zhuǎn)運(yùn)蛋白的谷氨酸積累, 從而影響抑郁的神經(jīng)元興奮性(Stepanichev et al., 2014)。另外, ucOCN也可通過調(diào)節(jié)神經(jīng)免疫相關(guān)基因表達(dá)來調(diào)節(jié)抑郁。ucOCN可上調(diào)海馬組織中PVT1表達(dá), 降低TNF-α、IL-1β和IL-6表達(dá)后通過作用于海馬組織蛋白激酶C (Protein kinase C, PKC)進(jìn)而上調(diào)BDNF表達(dá), 促進(jìn)神經(jīng)元再生及星型膠質(zhì)細(xì)胞活化, 減少TUNEL陽性細(xì)胞數(shù)量(Zhao, Ding, et al., 2019); 亦可激活A(yù)KT/mTOR炎癥途徑從而調(diào)節(jié)AKT等蛋白表達(dá), 促進(jìn)星型膠質(zhì)細(xì)胞、小膠質(zhì)細(xì)胞增加并抑制神經(jīng)元細(xì)胞凋亡, 改善抑郁樣行為。并且, 體外實(shí)驗(yàn)也證實(shí), ucOCN對Aβ-42損傷PC12細(xì)胞的保護(hù)作用是通過AKT/mTOR途徑進(jìn)行調(diào)控(單暢, 2019)。以上直接證據(jù)表明, 骨源性ucOCN通過介導(dǎo)AKT/mTOR/NF-κB炎癥途徑和炎癥細(xì)胞來調(diào)節(jié)海馬扣帶回星型膠質(zhì)細(xì)胞功能, 進(jìn)而調(diào)控抑郁發(fā)生。然而, ucOCN也可直接作用于IL-6、IL-10、IL-1β等表達(dá)(Millar et al., 2019), 并通過影響HPA軸、中性粒細(xì)胞數(shù)量等來調(diào)控抑郁發(fā)生, 那么ucOCN能否通過介導(dǎo)IL-6、IL-10等炎癥因子進(jìn)而調(diào)控抑郁發(fā)生尚值得后續(xù)探究。

1.4 ucOCN調(diào)節(jié)神經(jīng)再生

重度抑郁癥患者的腦成像發(fā)現(xiàn), 海馬齒狀回(Dentate gyrus, DG)等腦組織微細(xì)結(jié)構(gòu)退化和海馬體積變小, 這一研究驗(yàn)證了中樞神經(jīng)結(jié)構(gòu)退化在抑郁發(fā)生中的作用, 也催生了“抑郁癥神經(jīng)再生假說” (Bremner et al., 1995)。中樞側(cè)腦室室管膜下區(qū)(Subventricular, SVZ)和海馬DG顆粒下層區(qū)是目前研究證實(shí)的兩個(gè)存在神經(jīng)前體細(xì)胞和具有神經(jīng)再生潛能的區(qū)域(石旺清等, 2013)。海馬神經(jīng)再生障礙是抑郁發(fā)生的重要機(jī)制, 調(diào)控海馬神經(jīng)功能及促進(jìn)神經(jīng)干細(xì)胞增殖、分化、成熟后整合參與神經(jīng)環(huán)路可抗抑郁或改善抑郁樣行為(Santarelli et al., 2003)。后續(xù)研究發(fā)現(xiàn), 海馬為主的齒狀回顆粒下層區(qū)神經(jīng)發(fā)生減退被認(rèn)為是抑郁發(fā)生的最終通路(Duman, 2004)。慢性應(yīng)激是抑郁發(fā)生的誘導(dǎo)因素, 動(dòng)物研究中, 社交失敗等應(yīng)激源抑制神經(jīng)發(fā)生, 而抗抑郁可促進(jìn)海馬神經(jīng)再生(郭雨欣等, 2012)。但有研究卻發(fā)現(xiàn), 抑制神經(jīng)發(fā)生并不能導(dǎo)致抑郁發(fā)生。習(xí)得性無助抑郁模型的腦室壁下回神經(jīng)發(fā)生減退與抑郁行為表現(xiàn)并不相關(guān)(Vollmayr et al., 2003); 經(jīng)顱磁治療可逆轉(zhuǎn)應(yīng)激對抑郁癥大鼠HPA軸的影響, 但對中側(cè)腦室神經(jīng)元發(fā)生作用不顯著(Czéh et al., 2002); 并且, 阻斷神經(jīng)發(fā)生后, 單胺類抗抑郁藥物、ACTH釋放因子和血管升壓素藥物的效果不受影響(David et al., 2009)。在一項(xiàng)臨床研究中, 發(fā)現(xiàn)抗抑郁藥物對情緒的改善作用并不依賴于神經(jīng)再生(Bessa et al., 2009)。神經(jīng)干細(xì)胞主要存在于中側(cè)腦室壁的腦室下區(qū)和海馬齒狀回顆粒下層, 以上研究發(fā)現(xiàn)海馬區(qū)神經(jīng)再生是調(diào)控抑郁的關(guān)鍵, 而中側(cè)腦室壁的腦室下區(qū)的神經(jīng)再生卻無效。近年來, 探究T2DM神經(jīng)再生與認(rèn)知障礙相關(guān)性受到國內(nèi)學(xué)者關(guān)注。T2DM大鼠骨中Runx2表達(dá)下調(diào)后抑制ucOCN分泌, 進(jìn)而導(dǎo)致中腦和海馬神經(jīng)再生被抑制, 神經(jīng)元結(jié)構(gòu)和功能改變, 認(rèn)知功能(空間探索和學(xué)習(xí)記憶能力)受損(Gu et al., 2017)。T2DM加速認(rèn)知障礙及迅速發(fā)展為癡呆癥, 導(dǎo)致智力活動(dòng)、執(zhí)行能力和處理速度下降(Yu et al., 2020)。然而, T2DM患者血清ucOCN水平顯著下降, 這是引起認(rèn)知功能障礙, 甚至抑郁癥、癡呆癥及其他精神疾病的原因機(jī)制。

抑郁發(fā)生后大腦神經(jīng)再生障礙會導(dǎo)致學(xué)習(xí)記憶能力下降等表征(López et al., 2016)。ucOCN作為骨源性特異蛋白, ucOCN–/–小鼠雙皮質(zhì)素(Dipcortin, DCX)+和BrdU+神經(jīng)元數(shù)量均顯著減少, 當(dāng)母體基因型為ucOCN–/–時(shí), 這種減少更為嚴(yán)重; 發(fā)現(xiàn)ucOCN的敲除促進(jìn)海馬神經(jīng)細(xì)胞凋亡, 減緩神經(jīng)發(fā)生是成年抑郁樣小鼠海馬依賴性學(xué)習(xí)能力下降的主因(Oury et al., 2015)。ucOCN基因敲除導(dǎo)致的神經(jīng)元數(shù)量減少、再生能力下降是導(dǎo)致抑郁發(fā)生的主因。其分子機(jī)制與骨中ucOCN表達(dá)下調(diào)入血后抑制海馬齒狀回Notch途徑(袁萍, 2020)和磷酸二酯酶9 (Phosphodiesterase 9, PDE9)-環(huán)磷酸鳥苷(Cyclic guanosine phosphate, cGMP)-cGMP依賴性蛋白激酶(cGMP dependent protein kinase, PKG)途徑(校歡, 2020)密切相關(guān)。兩條信號途徑被抑制后下調(diào)靶基因BDNF等表達(dá), 導(dǎo)致小鼠海馬齒狀回中BrdU、DCX和BrdU/NeuN陽性細(xì)胞數(shù)量下降, 并顯著抑制NSCs細(xì)胞活力及其增殖, 導(dǎo)致抑郁發(fā)生, 實(shí)現(xiàn)“骨?腦Crosstalk”, 上述機(jī)制匯總可見表1。

2 ucOCN介導(dǎo)“骨?腦Crosstalk”在運(yùn)動(dòng)抗抑郁中的作用機(jī)制

2.1 ucOCN調(diào)節(jié)神經(jīng)遞質(zhì)在運(yùn)動(dòng)抗抑郁中的作用

整合生理學(xué)的觀點(diǎn)認(rèn)為, 機(jī)體各器官組織之間是相互作用、影響。骨既是運(yùn)動(dòng)器官, 亦是重要代謝器官, 因此運(yùn)動(dòng)抗抑郁的積極效應(yīng)均可從骨中找到答案。運(yùn)動(dòng)抗抑郁中單胺類神經(jīng)遞質(zhì)分泌增加(Lee et al., 2019)。有研究發(fā)現(xiàn), 慢性中等不可預(yù)知應(yīng)激抑郁大鼠不同腦區(qū)內(nèi)單胺類神經(jīng)遞質(zhì)(如NE、DA、5-HT和5-羥吲哚乙酸)水平顯著下降, 而長期游泳訓(xùn)練在改善大鼠抑郁表征的同時(shí)也會顯著恢復(fù)和增加單胺類神經(jīng)遞質(zhì)的分泌(崔冬雪, 2005)?；诖x組學(xué)分析, 不同運(yùn)動(dòng)促進(jìn)CUMS抑郁模型大鼠血漿中5-HT、NE、DA等分泌從而改善抑郁(張波, 2019)。而ucOCN是力學(xué)刺激敏感基因, 運(yùn)動(dòng)促進(jìn)骨中ucOCN表達(dá)并進(jìn)而調(diào)控抑郁改善, 臨床研究中, 每周3～5次、每次35min的慢跑有氧運(yùn)動(dòng)使得成年抑郁癥患者血清GABA含量下降且谷氨酸含量升高, 進(jìn)而改善抑郁樣行為; 并且, 血清ucOCN濃度升高與GABA濃度下降和谷氨酸濃度升高呈顯著正相關(guān)(杜遠(yuǎn), 2019)。表明, 運(yùn)動(dòng)促進(jìn)抑郁癥患者血清ucOCN高表達(dá)同時(shí)亦抑制GABA并促進(jìn)谷氨酸等神經(jīng)遞質(zhì)分泌, 改善抑郁樣行為。隨著對ucOCN研究深入, 發(fā)現(xiàn)運(yùn)動(dòng)上調(diào)抑郁癥大鼠骨中ucOCN表達(dá)并促進(jìn)血清5-HT、DA分泌, 從而改善其抑郁樣行為(Zoch et al., 2016)。Obri等(2018)研究也發(fā)現(xiàn), 8周跑臺訓(xùn)練上調(diào)CUMS大鼠骨中ucOCN表達(dá)并釋放入血后, 促進(jìn)5-HT并抑制GABA等分泌, 從而改善其抑郁樣行為。另外, 2個(gè)月跑臺訓(xùn)練(30min/天)可顯著提高T2DM合并抑郁癥小鼠血清ucOCN水平, 改善其抑郁樣行為(Rentz et al., 2020)。其機(jī)制與運(yùn)動(dòng)激活ucOCN及其介導(dǎo)Gpr158/BDNF途徑, 促進(jìn)神經(jīng)遞質(zhì)分泌, 進(jìn)而調(diào)控抑郁等認(rèn)知障礙發(fā)生密切相關(guān)。提示, ucOCN介導(dǎo)的單胺類神經(jīng)遞質(zhì)分泌實(shí)現(xiàn)了“骨?腦Crosstalk”從而介導(dǎo)運(yùn)動(dòng)抗抑郁?；诠侵衭cOCN介導(dǎo)抗抑郁的作用及其運(yùn)動(dòng)敏感性, 運(yùn)動(dòng)誘導(dǎo)骨中ucOCN表達(dá)或激活后, 促進(jìn)單胺類神經(jīng)遞質(zhì)分泌進(jìn)而抗抑郁的機(jī)制與ucOCN促進(jìn)IL-6表達(dá)及激活胰島素?胰島素受體途徑有關(guān), IL-6及胰島素分泌增加經(jīng)過血液循環(huán)、血腦屏障進(jìn)入腦組織促進(jìn)5-HT、DA并抑制GABA等單胺類神經(jīng)遞質(zhì)分泌, 進(jìn)而改善抑郁(Fordahl & Jones, 2017; Muhammad et al., 2013)。

表1 ucOCN介導(dǎo)“骨?腦Crosstalk”在抑郁發(fā)生中的作用機(jī)制匯總表

注：羧化不全骨鈣素(ucOCN), 血清糖皮質(zhì)激素(GC), 下丘腦?垂體?腎上腺軸(HPA軸), 促腎上腺皮質(zhì)激素(ACTH), G蛋白偶聯(lián)受體C家族A成員6(GPRC6A), 胰島素抵抗(IR), 促腎上腺皮質(zhì)激素釋放激素(CRH), 核轉(zhuǎn)錄因子-κB (NF-κB), 星形膠質(zhì)細(xì)胞補(bǔ)體C3, 谷氨酸受體AMPAR受體, 肌醇1, 4, 5-三磷酸受體2型(IP3Rs2), 三磷酸腺苷受體(P2X2), 5-HT轉(zhuǎn)運(yùn)體基因連鎖多態(tài)性區(qū)域(5-HTTLPR), N-甲基-D-天冬氨酸(NMDA)。

2.2 ucOCN調(diào)節(jié)神經(jīng)內(nèi)分泌在運(yùn)動(dòng)抗抑郁中的作用

神經(jīng)內(nèi)分泌介導(dǎo)抑郁發(fā)生和減緩, 而運(yùn)動(dòng)作為一種應(yīng)激反應(yīng)可激活HPA軸促進(jìn)GC、ACTH等激素分泌, 同時(shí)亦可增加HPA軸對慢性應(yīng)激的適應(yīng)(Hegberg et al., 2019)。Pang等(2013a)在研究體育鍛煉對酒精戒斷康復(fù)期間的抑郁樣行為影響時(shí), 發(fā)現(xiàn)6周自主跑輪運(yùn)動(dòng)可顯著改善酒精戒斷康復(fù)期間小鼠的抑郁樣行為; 后續(xù), Pang等利用游泳訓(xùn)練(6周、6天/周、每次50 min)對該小鼠進(jìn)行運(yùn)動(dòng)干預(yù), 發(fā)現(xiàn)酒精戒斷康復(fù)階段小鼠HPA軸被激活, 血清中ACTH、GC、CRH和促視神經(jīng)黑皮質(zhì)激素分泌增加, 小鼠抑郁行為得到顯著改善(Pang et al., 2013b)。HPA軸調(diào)控抑郁發(fā)生、改善, 4周跑輪運(yùn)動(dòng)加快小鼠在約束壓力下皮質(zhì)醇、ACTH、鹽皮質(zhì)激素到達(dá)峰值時(shí)間及加快其衰減; 自主跑輪運(yùn)動(dòng)改善全身性注射地塞米松引起的腎上腺變小和ACTH、GC、皮質(zhì)醇降低, 進(jìn)而改善抑郁(Hare et al., 2014)。臨床研究中, 對80名肥胖青少年進(jìn)行3個(gè)月有氧運(yùn)動(dòng)減肥同時(shí), 發(fā)現(xiàn)肥胖青少年血清ucOCN水平與尿皮質(zhì)醇和抑郁樣行為改善呈顯著正相關(guān)(Okbay Güne? et al., 2017)。6周有氧運(yùn)動(dòng)訓(xùn)練可顯著激活重度抑郁癥患者HPA軸, 提高血清皮質(zhì)醇濃度, 改善抑郁(Gerber et al., 2020)。而對接受過乳腺癌手術(shù)且伴有抑郁樣行為的85名女性進(jìn)行6個(gè)月運(yùn)動(dòng)干預(yù)后, 發(fā)現(xiàn)HPA軸功能顯著改善, 唾液皮質(zhì)醇顯著增加, 且伴隨總白細(xì)胞、中性粒細(xì)胞和淋巴細(xì)胞等顯著下降(Saxton et al., 2014)。以上動(dòng)物和臨床研究均提示, 運(yùn)動(dòng)通過激活HPA軸, 促進(jìn)ACTH、GC、鹽皮質(zhì)激素、皮質(zhì)醇等分泌進(jìn)而改善抑郁行為。其機(jī)制與心鈉素(Atrial natriuretic peptide, ANP)受體、GC受體、鹽皮質(zhì)激素受體等mRNA表達(dá)增加密切相關(guān)。ucOCN介導(dǎo)抑郁且在運(yùn)動(dòng)應(yīng)激下表達(dá)顯著上調(diào), 其表達(dá)上調(diào)后促進(jìn)ACTH、GC和鹽皮質(zhì)激素分泌, 血清濃度增加(Nella et al., 2016); 亦可激活HPA軸功能, 提高血清皮質(zhì)醇、ACTH濃度(Shobana et al., 2019)。而17名抑郁癥患者進(jìn)行12周跑步訓(xùn)練后, 血清ucOCN顯著升高且GC、鹽皮質(zhì)激素和ACTH濃度亦顯著升高(Tsikirai et al., 2020); 但也有研究發(fā)現(xiàn), 12周跑步運(yùn)動(dòng)不能顯著提高肺癌患者血清ucOCN和GC、ACTH等濃度, 抑郁樣行為變化不明顯(Cavalheri et al., 2019)。以上結(jié)果差異, 說明運(yùn)動(dòng)在上調(diào)抑郁癥患者ucOCN表達(dá)及GC等相關(guān)激素分泌上存在時(shí)間差異, 并與被試對象不同有關(guān)?，F(xiàn)有研究證實(shí)ucOCN介導(dǎo)ACTH、GC、HPA軸等實(shí)現(xiàn)了運(yùn)動(dòng)抗抑郁中的“骨?腦Crosstalk”, 但目前運(yùn)動(dòng)方式單一, 多種運(yùn)動(dòng)抗抑郁作用的對比或聯(lián)合干預(yù)研究尚待補(bǔ)充。

2.3 ucOCN介導(dǎo)神經(jīng)免疫機(jī)制在運(yùn)動(dòng)抗抑郁中的作用

神經(jīng)免疫可直接參與運(yùn)動(dòng)抗抑郁, 亦可介導(dǎo)HPA軸等神經(jīng)內(nèi)分泌來發(fā)揮作用, 由此其在運(yùn)動(dòng)抗抑郁中的作用得到特別關(guān)注(胡亮等, 2019)。近年來, 運(yùn)動(dòng)抗抑郁的神經(jīng)免疫機(jī)制集中在：細(xì)胞或體液免疫介導(dǎo)氧化應(yīng)激或炎癥反應(yīng)進(jìn)而改善抑郁行為上(Kohut et al., 2006)。如有氧跑臺運(yùn)動(dòng)可通過誘導(dǎo)內(nèi)源性硫化氫(Hydrogen sulfide, H2S)氣體信號, 并通過抑制Toll樣受體4 (Toll-like receptors 4, TLR4)介導(dǎo)的髓樣分化因子(Myeloid differentiation factor 88, MyD88)/NF-кB炎癥信號途徑, 從而改善慢性不可預(yù)知應(yīng)激(CUMS)抑郁小鼠抑郁樣行為, 促進(jìn)海馬神經(jīng)元修復(fù); 并且TLR4抑制劑的效果與跑臺運(yùn)動(dòng)效果一致, 均可抑制抑郁小鼠血液與海馬組織炎癥反應(yīng)(屈紅林, 2019)。Kohut等發(fā)現(xiàn), 有氧運(yùn)動(dòng)通過降低血清中IL-6、IL-18、TNF-α、C-反應(yīng)蛋白(C-reactive protein, CRP)等炎癥因子來改善慢性應(yīng)激引發(fā)的抑郁(Eyre et al., 2013)。6次/周、共18周的自行車運(yùn)動(dòng)可顯著降低血清IL-6和IL-18水平(Zhao et al., 2016); 12周慢跑亦可顯著抑制慢性堵塞性肺疾病(Chronic obstructive pulmonary disease, COPD)合并抑郁癥患者血清中TNF-α、IL-4、IL-6和CRP炎癥因子水平(ABD EL-KADER & Al-Jiffri, 2016), 進(jìn)而改善抑郁樣行為。動(dòng)物研究中, Algaidi等(2019)利用2周強(qiáng)迫游泳建立抑郁癥Wistar大鼠模型, 3周自主跑輪運(yùn)動(dòng)干預(yù)后利用免疫組化對大鼠齒狀回、內(nèi)側(cè)前額葉皮層等部位的巨噬細(xì)胞遷移抑制因子(Macrophage migration inhibitory factor, MIF)、IL-6和BDNF表達(dá)進(jìn)行檢測, 發(fā)現(xiàn)MIF和IL-6表達(dá)下調(diào)后, 靶基因BDNF等激活并改善大鼠抑郁樣行為。說明, 運(yùn)動(dòng)改善抑郁與炎癥因子表達(dá)下調(diào)顯著相關(guān), 但以上研究集中在有氧運(yùn)動(dòng), 而抗阻訓(xùn)練或有氧運(yùn)動(dòng)聯(lián)合抗阻訓(xùn)練在改善抑郁上的作用效果尚不清楚。ucOCN介導(dǎo)神經(jīng)免疫調(diào)節(jié)抑郁發(fā)生和減緩, 體育科學(xué)領(lǐng)域內(nèi), 運(yùn)動(dòng)通過提高OB活性來上調(diào)ucOCN表達(dá), 進(jìn)而抑制IL-6、IL-18和TNF-α等炎癥因子的mRNA表達(dá), 可顯著改善抑郁樣行為(Napoli et al., 2014)。其機(jī)制與ucOCN表達(dá)上調(diào)可通過激活ERK途徑和STAT途徑來下調(diào)海馬中IL-6和IL-8mRNA及蛋白表達(dá), 進(jìn)而通過丙二醛(Malondialdehyde, MDA)/超氧化物歧化酶(Superoxide dismutase, SOD)/核因子類紅細(xì)胞衍生的2-樣2 (Nuclear factor erythroid- derived 2-like 2, Nrf2)/血紅素加氧酶1 (Heme oxygenase 1, HO1)途徑上調(diào)VGF和BDNF表達(dá)密切相關(guān)(Millar et al., 2020)。當(dāng)利用8周有氧運(yùn)動(dòng)對伴隨有抑郁表現(xiàn)的大學(xué)生進(jìn)行干預(yù)時(shí), 發(fā)現(xiàn)血清中表達(dá)上調(diào)的ucOCN與下調(diào)的TNF-α和CRP呈顯著負(fù)相關(guān), 且其抑郁行為被顯著改善(Huang et al., 2020; 許靜等, 2016)。以上研究揭示, ucOCN通過調(diào)控腦組織神經(jīng)免疫實(shí)現(xiàn)了“骨?腦Crosstalk”, 從而介導(dǎo)運(yùn)動(dòng)抗抑郁。

ucOCN介導(dǎo)神經(jīng)免疫實(shí)現(xiàn)“骨?腦Crosstalk”發(fā)揮運(yùn)動(dòng)抗抑郁, 其機(jī)制與ucOCN介導(dǎo)的PFC抗炎能力激活神經(jīng)生長因子(Nerve growth factor, NGF)?酪氨酸蛋白激酶A (Tyrosine protein kinase A, TrkA) (崔建梅等, 2020)、過氧化物酶體增殖物激活受體-γ共激活因子-1α (Peroxisome proliferator- activated receptorγcoactivator-1α, PGC-1α)/Ⅲ型纖連蛋白域蛋白5 (type Ⅲ domain-containing protein 5, FNDC5)/BDNF (陳蓉, 2019)、miRNAs/ PGC-1α/賴氨酸乙酰轉(zhuǎn)移酶(Lysine Acetyltransferase, KATs) (羅佳, 2019)等信號途徑調(diào)控抑郁發(fā)生、改善密切相關(guān)。而ucOCN作為力學(xué)刺激敏感基因, 運(yùn)動(dòng)上調(diào)ucOCN表達(dá)后可下調(diào)抑郁小鼠海馬中IL-6、PGC-1α、miRNA-130b等mRNA表達(dá)進(jìn)而調(diào)控抑郁。

圖1 ucOCN介導(dǎo)“骨?腦Crosstalk”在運(yùn)動(dòng)抗抑郁中的作用機(jī)制示意圖

注：ucOCN是OB中分化的特異性蛋白。神經(jīng)元5-羥色胺(5-HT), 腦源性神經(jīng)營養(yǎng)因子(BDNF), 多巴胺(DA)、γ-氨基丁酸(GABA), 糖皮質(zhì)激素(GC), 促腎上腺皮質(zhì)激素釋放激素(CRH), 巨噬細(xì)胞遷移抑制因子(MIF), C-反應(yīng)蛋白(CRP), 白介素6 (IL-6), 腫瘤壞死因子-α (TNF-α)。運(yùn)動(dòng)促進(jìn)骨中ucOCN表達(dá), 通過血腦屏障入腦后, 作用于腦中海馬、前額葉等腦區(qū), 促進(jìn)BDNF、DA、5-HT、NE, 抑制GABA等神經(jīng)遞質(zhì)表達(dá), 同時(shí)減少IL-6水平; ucOCN通過作用于下丘腦等腦區(qū)來激活HPA軸, 促進(jìn)ACTH、CRH等基因表達(dá), 同時(shí)通過神經(jīng)內(nèi)分泌循環(huán)作用降低炎癥因子水平, 減緩神經(jīng)炎癥反應(yīng)。

3 小結(jié)與展望

ucOCN作為骨源性力學(xué)刺激敏感基因, 運(yùn)動(dòng)上調(diào)骨中ucOCN表達(dá)或活性, 以轉(zhuǎn)錄輔激活作用調(diào)節(jié)單胺類神經(jīng)遞質(zhì)分泌、神經(jīng)內(nèi)分泌功能和神經(jīng)免疫等, 進(jìn)而通過多種途徑作用于海馬等腦組織, 以“骨?腦Crosstalk”形式改善HPA軸功能、減緩中樞炎癥反應(yīng)、促進(jìn)神經(jīng)元細(xì)胞再生, 進(jìn)而發(fā)揮抗抑郁效應(yīng)?；谀壳跋嚓P(guān)研究, 對ucOCN介導(dǎo)的“骨?腦Crosstalk” “對話”模式進(jìn)行分析, 提出了運(yùn)動(dòng)抗抑郁中的ucOCN介導(dǎo)途徑, 部分機(jī)制如圖1所示。雖然綜述目前相關(guān)研究, 發(fā)現(xiàn)了“骨?腦Crosstalk”的有利證據(jù), 但仍存在幾個(gè)問題亟待進(jìn)一步的探究：(1) ucOCN介導(dǎo)單胺類神經(jīng)遞質(zhì)或神經(jīng)內(nèi)分泌進(jìn)而調(diào)控運(yùn)動(dòng)抗抑郁的具體分子機(jī)制網(wǎng)絡(luò)尚待揭示。(2)運(yùn)動(dòng)促進(jìn)神經(jīng)再生, ucOCN能否介導(dǎo)神經(jīng)再生從而介導(dǎo)運(yùn)動(dòng)抗抑郁？(3)骨骼分泌物或特異性表達(dá)因子較多, 目前僅確認(rèn)了ucOCN在運(yùn)動(dòng)抗抑郁中的作用, 未來研究需要進(jìn)一步篩選可能透過血腦屏障進(jìn)入腦組織發(fā)揮作用的骨分泌或表達(dá)特異性小分子物質(zhì); 或進(jìn)一步探討血腦屏障上的相應(yīng)受體, 并探討其機(jī)制。(4)運(yùn)動(dòng)激活骨中多種基因表達(dá), 但研究發(fā)現(xiàn)可介導(dǎo)“骨?腦Crosstalk”的基因并不多。相信, 深入探究和驗(yàn)證以上問題, 將從“骨?腦Crosstalk”的視角上更深層次的解析運(yùn)動(dòng)抗抑郁及運(yùn)動(dòng)健腦的生物學(xué)機(jī)制網(wǎng)絡(luò)。

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The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise

CHEN XiangHe1, LI WenXiu1, LIU Bo1, YIN RongBin2

(1College of Physical Education, Yangzhou University, Yangzhou 225127, China)(2College of Physical Education, Soochow University, Suzhou 215000, China)

Undercarboxylated osteocalcin (ucOCN) is a specific protein secreted by osteoblasts in bone. It has attracted attention in the field of neuroscience because of its important role in regulating neurodevelopment and neuroplasticity. “Bone-Brain Crosstalk” is a bone endocrine-nerve mediated response system. ucOCN modulate the monoamine neurotransmitters, neuroendocrine, neuroimmunity, nerve regeneration and gene expression after passing through the blood-brain barrier. ucOCN further acts on the hippocampus CA3 area, cingulate gyrus and other brain areas to regulate the occurrence and reduction of depression. As a bone-derived mechanical stimulation sensitive gene, ucOCN enters the blood circulation after exercise upregulating its expression, and mediates 5-HT/GABA secretion, HPA axis function, inflammation, neurotrophic factor (BDNF, etc.) expression or signal pathways (such as GSK3β/β-catenin, TLR4/miR- 223/NLRP3, etc.) activation to achieve the “Bone-mediated brain” and mediate the antidepressant effect of exercise. This review emphasized the anti-depression effect of exercise through the discussion and sorting out of the mechanism of ucOCN-mediated brain function changes. On one hand, it is helpful to have a deeper understanding of bone endocrine function, on the other hand, it provides a new theoretical basis and research ideas for the occurrence and improvement of depression and the study of exercise anti-depression.

undercarboxylated osteocalcin, bone, brain, exercise, depression

B845

2021-04-28

* 國家社會科學(xué)基金教育學(xué)青年課題《精準(zhǔn)運(yùn)動(dòng)改善青少年抑郁癥的模式構(gòu)建及應(yīng)用研究》(CLA200279)。

陳祥和, E-mail: huashixh@163.com