2016年9月，《Cerebral Cortex》雜志在線發(fā)表了中國(guó)科學(xué)院腦科學(xué)與智能技術(shù)卓越創(chuàng)新中心, 第三軍醫(yī)大學(xué)腦科學(xué)研究中心諶小維課題組題為“Sensory Response of Transplanted Astrocytes in AdultMammalian Cortex In Vivo”的研究論文，研究以封面文章的形式發(fā)表。研究利用雙光子活體鈣成像以及雙束掃描電鏡三維重構(gòu)等技術(shù)，證實(shí)移植進(jìn)入成年小鼠大腦皮層的星形膠質(zhì)細(xì)胞不僅在形態(tài)，而且在功能上可整合進(jìn)入宿主神經(jīng)網(wǎng)絡(luò)，為星形膠質(zhì)細(xì)胞缺陷相關(guān)疾病的治療提供了新的思路。第三軍醫(yī)大學(xué)腦科學(xué)研究中心張寬博士和第三軍醫(yī)大學(xué)勞動(dòng)衛(wèi)生學(xué)教研室陳純海博士為論文共同第一作者，諶小維研究員和周舟副研究員為論文共同通訊作者。

作為一種重要的神經(jīng)膠質(zhì)細(xì)胞類型，星形膠質(zhì)細(xì)胞在神經(jīng)網(wǎng)絡(luò)的信息整合過(guò)程中起到關(guān)鍵作用。例如，其可根據(jù)神經(jīng)元的活動(dòng)情況，來(lái)控制血管的收縮或舒張，從而對(duì)腦部氧含量的分配進(jìn)行調(diào)控。但伴隨著衰老以及各種神經(jīng)及精神疾病的發(fā)生，星形膠質(zhì)細(xì)胞會(huì)出現(xiàn)不同程度的功能損傷。越來(lái)越多的研究顯示，星形膠質(zhì)細(xì)胞移植確實(shí)可以對(duì)動(dòng)物的認(rèn)知和行為功能異常起到改善作用。并且有研究表明，移植星形膠質(zhì)細(xì)胞的形態(tài)不僅與宿主細(xì)胞類似，而且還具有和宿主星形膠質(zhì)細(xì)胞相同的分子表達(dá)特征。這些結(jié)果提示星形膠質(zhì)細(xì)胞移植可以作為治療星形膠質(zhì)細(xì)胞功能障礙疾病的潛在手段。但是，目前有關(guān)移植膠質(zhì)細(xì)胞的功能整合研究均停留在體外腦片的研究上。移植后星形膠質(zhì)細(xì)胞是否可以在功能上整合進(jìn)入宿主神經(jīng)網(wǎng)絡(luò)，并且參與信息處理目前還不清楚。

在本課題中，研究人員首先用雙光子在體成像技術(shù)，在移植后不同時(shí)間點(diǎn)，對(duì)移植進(jìn)入成年小鼠體感皮層的星形膠質(zhì)前體細(xì)胞進(jìn)行成像，以觀察移植后星形膠質(zhì)前體細(xì)胞在小鼠體感皮層的分化和存活情況。結(jié)果表明，移植進(jìn)入成年小鼠皮層的星形膠質(zhì)前體細(xì)胞在移植后12周便可分化為成熟的星形膠質(zhì)細(xì)胞并且能夠至少存活一年以上。另外，移植進(jìn)入皮層的星形膠質(zhì)細(xì)胞還能包繞血管，形成“終足”樣結(jié)構(gòu)。

已經(jīng)知道，成熟星形膠質(zhì)細(xì)胞可參與神經(jīng)網(wǎng)絡(luò)的功能信息整合過(guò)程。移植進(jìn)入皮層的星形膠質(zhì)細(xì)胞是否也可以在功能上整合進(jìn)入宿主神經(jīng)網(wǎng)絡(luò)?為回答這一問(wèn)題，研究人員利用在體雙光子鈣成像的方法，在活體小鼠體感皮層觀察了移植星形膠質(zhì)細(xì)胞在宿主神經(jīng)網(wǎng)絡(luò)的功能整合情況。研究發(fā)現(xiàn)，在移植后12周，移植星形膠質(zhì)細(xì)胞便可以對(duì)小鼠的“足底電擊”刺激產(chǎn)生“鈣應(yīng)答”反應(yīng)。移植星形膠質(zhì)細(xì)胞的鈣反應(yīng)幅度和潛伏期與宿主星形膠質(zhì)細(xì)胞相比沒(méi)有明顯差異。

進(jìn)一步研究發(fā)現(xiàn)，移植星形膠質(zhì)細(xì)胞可以表達(dá)乙酰膽堿能受體，并且與宿主星形膠質(zhì)細(xì)胞相同，移植星形膠質(zhì)細(xì)胞上“足底電擊”引起的鈣信號(hào)是由乙酰膽堿能受體介導(dǎo)。利用雙束掃描電鏡三維重構(gòu)技術(shù)對(duì)移植星形膠質(zhì)細(xì)胞的突起進(jìn)行了微尺度三維重構(gòu)，發(fā)現(xiàn)移植星形膠質(zhì)細(xì)胞不僅能和宿主神經(jīng)元形成三突觸結(jié)構(gòu)，還可以與宿主神經(jīng)元直接形成突觸結(jié)構(gòu)。這一結(jié)果為移植星形膠質(zhì)細(xì)胞的功能整合提供了形態(tài)學(xué)基礎(chǔ)。

研究發(fā)現(xiàn)移植星形膠質(zhì)細(xì)胞可以在形態(tài)以及功能上整合進(jìn)入成年動(dòng)物皮層。此項(xiàng)研究為治療星形膠質(zhì)細(xì)胞缺陷有關(guān)的大腦疾病提供了潛在治療手段。

封面圖片：綠色熒光蛋白(綠色)和GFAP(紅色)共標(biāo)的移植星形膠質(zhì)細(xì)胞在移植后12周可分布于成年小鼠皮層并呈現(xiàn)成熟星形膠質(zhì)細(xì)胞的形態(tài)。宿主星形膠質(zhì)細(xì)胞為GFAP(紅色)單標(biāo)的細(xì)胞。DAPI(藍(lán)色)著色結(jié)構(gòu)為細(xì)胞核。

原文鏈接：

Sensory response of transplanted astrocytes in adult mammalian cortex in vivo

原文摘要：

Glial precursor transplantation provides a potential therapy for brain disorders. Before its clinical application, experimental evidence needs to indicate that engrafted glial cells are functionally incorporated into the existing circuits and become essential partners of neurons for executing fundamental brain functions. While previous experiments supporting for their functional integration have been obtained under in vitro conditions using slice preparations, in vivo evidence for such integration is still lacking. Here, we utilized in vivo two-photon Ca2 imaging along with immunohistochemistry, fluorescent indicator labeling-based axon tracing and correlated light/electron microscopy to analyze the profiles and the functional status of glial precursor cell-derived astrocytes in adult mouse neocortex. We show that after being transplanted into somatosensory cortex, precursor-derived astrocytes are able to survive for more than a year and respond with Ca2 signals to sensory stimulation. These sensory-evoked responses are mediated by functionally-expressed nicotinic receptors and newly-established synaptic contacts with the host cholinergic afferents. Our results provide in vivo evidence for a functional integration of transplanted astrocytes into adult mammalian neocortex, representing a proof-of-principle for sensory cortex remodeling through addition of essential neural elements. Moreover, we provide strong support for the use of glial precursor transplantation to understand glia-related neural development in vivo.