2014年諾貝爾生理學或醫(yī)學獎（構(gòu)成大腦定位系統(tǒng)的細胞）

大腦中的“定位系統(tǒng)”——2014年諾貝爾生理學或醫(yī)學獎簡介

王可，張婷，王曉民

（首都醫(yī)科大學基礎(chǔ)醫(yī)學院神經(jīng)生物學系教育部神經(jīng)變性病重點實驗室北京市腦重大疾病研究院北京市腦重大疾病重點實驗室，北京100069）

大鼠多通道在體記錄

王一男，唐永強，潘璟瑋，等

熱點追蹤

2014年諾貝爾生理學或醫(yī)學獎（構(gòu)成大腦定位系統(tǒng)的細胞）

·編者按·

2014年10月6日，瑞典卡羅琳醫(yī)學院在斯德哥爾摩宣布，將2014年諾貝爾生理學或醫(yī)學獎授予擁有美國和英國國籍的科學家約翰奧基夫（John O'Keefe）以及兩位挪威科學家梅-布利特·莫澤（May-Britt Moser）和愛德華·莫澤（Edvard I. Moser），以表彰他們在發(fā)現(xiàn)構(gòu)建大腦空間定位系統(tǒng)的重要細胞方面所做出的杰出貢獻.他們的研究成果揭示了特化細胞如何協(xié)作并執(zhí)行更高的認知功能，為人類高級認知功能提供了細胞基礎(chǔ)，開啟了人類對記憶、思考等認知過程理解的新篇章.

位置感知和導航能力是大腦的基本功能.位置感知能力賦予人類認識環(huán)境中自身的位置以及其他物體的相對位置，而導航能力則是在前期運動和位置記憶的基礎(chǔ)上，對距離及方向認知進行整合，從而實現(xiàn)精確定位和路線查找.以上3位科學家首次發(fā)現(xiàn)了構(gòu)成大腦定位系統(tǒng)的細胞并揭示了其潛在的功能.John O'Keefe發(fā)現(xiàn)了定位系統(tǒng)中的第一個組成細胞，即位于大腦海馬區(qū)的一類錐體神經(jīng)元，被稱為“位置細胞”（Place cell）.該細胞使大腦能夠?qū)⑻囟ǖ奶卣餍畔⑴c相應(yīng)空間位置聯(lián)系起來，形成空間位置記憶.May-Britt Moser和Edvard I. Moser夫婦在大腦的內(nèi)嗅皮層發(fā)現(xiàn)了大腦定位系統(tǒng)的另一關(guān)鍵組成細胞——“網(wǎng)格細胞”（Grid cell）.網(wǎng)格細胞將空間位置進行相應(yīng)的坐標標記，從而實現(xiàn)動物的精確定位及路徑尋找.所以當大腦擁有了網(wǎng)格細胞制定的坐標系統(tǒng)以及位置細胞構(gòu)建的位置特征信息，就形成了相對完整的腦內(nèi)“地圖”，實現(xiàn)了內(nèi)置GPS的功能.

空間識別及記憶功能喪失是認知功能障礙性疾病的主要臨床表現(xiàn)，如阿爾茨海默?。ˋlzheimer's disease，AD），患病初期就出現(xiàn)了迷路、無法辨識周邊環(huán)境等癥狀.因此，該研究有助于理解神經(jīng)精神疾病中腦回路異常的機制，對腦重大疾病的診斷和治療提供新的思路.Morser夫婦及John O'Keefe均指出Place cell與Grid cell，以及之前發(fā)現(xiàn)的Boundary cell和Head direction cell具有廣泛的功能聯(lián)系，這些神經(jīng)細胞間的交互作用，以及內(nèi)嗅皮質(zhì)與海馬之間的環(huán)路研究對探索大腦的空間記憶功能具有重要意義.

本專題得到了楊雄里院士（復(fù)旦大學腦科學研究院）、林龍年教授（華東師范大學腦功能基因組學研究所）的大力支持.

·熱點數(shù)據(jù)排行·

截至2015年2月11日，中國知網(wǎng)（CNKI）和Web of Science（WOS）的數(shù)據(jù)報告顯示，有關(guān)大腦空間定位系統(tǒng)研究的期刊文獻分別為13與807條，本刊將相關(guān)數(shù)據(jù)按照：研究機構(gòu)發(fā)文數(shù)、作者發(fā)文數(shù)、期刊發(fā)文數(shù)、被引用頻次進行排行，結(jié)果如下.

研究機構(gòu)發(fā)文數(shù)量排名（CNKI）

研究機構(gòu)發(fā)文數(shù)量排名（WOS）

作者發(fā)文數(shù)量排名（CNKI）

作者發(fā)文數(shù)量排名（CNKI）

期刊發(fā)文數(shù)量排名（CNKI）

期刊發(fā)文數(shù)量排名（WOS）

根據(jù)中國知網(wǎng)（CNKI）數(shù)據(jù)報告，有關(guān)大腦空間定位系統(tǒng)研究的高被引論文排行結(jié)果如下.

國內(nèi)數(shù)據(jù)庫高被引論文排行

根據(jù)Web of Science統(tǒng)計數(shù)據(jù)，有關(guān)大腦空間定位系統(tǒng)研究的高被引論文排行結(jié)果如下.

國外數(shù)據(jù)庫高被引論文排行

大腦中的“定位系統(tǒng)”——2014年諾貝爾生理學或醫(yī)學獎簡介*

王可，張婷，王曉民

（首都醫(yī)科大學基礎(chǔ)醫(yī)學院神經(jīng)生物學系教育部神經(jīng)變性病重點實驗室北京市腦重大疾病研究院北京市腦重大疾病重點實驗室，北京100069）

2014年10月6日，瑞典卡羅林斯卡醫(yī)學院宣布，將本年度諾貝爾生理學或醫(yī)學獎授予擁有美國和英國國籍的科學家約翰·奧基夫（John O'Keefe）及兩位挪威科學家梅一布里特·莫澤（May-Britt Moser）和愛德華·莫澤（Edvard I. Moser），表彰他們發(fā)現(xiàn)了大腦中的“內(nèi)置GPS（global positioning system）”——定位系統(tǒng)，這不僅使自然界生物可以在空間中進行自我定位，同時也為人類高級認知功能提供了細胞基礎(chǔ).

人們?nèi)绾沃雷约旱奈恢?？如何從一個地方到另一個地方？如何在大腦中儲存方位信息，以便下一次能夠找到相同路徑？自然界的生物總是能在好奇心驅(qū)使探尋外周世界的同時牢記自己回家的路.無論從動物的本能覓食、遷徙行為，還是到經(jīng)訓練后的老馬識途、飛鴿傳書等技能，都展示了在進化中自然界賦予大腦神奇的定位功能.那么究竟大腦是如何實現(xiàn)對自身定位呢？以上 3位科學家首次發(fā)現(xiàn)了構(gòu)成大腦定位系統(tǒng)的細胞并揭示了其潛在的功能.John O'Keefe發(fā)現(xiàn)了定位系統(tǒng)中的第一個組成細胞，即位于大腦海馬區(qū)的一類錐體神經(jīng)元，稱“位置細胞”（Place cell）.他的研究中指出動物行走到某個特定位置時，對應(yīng)一些特定Place cell激活，當行走到其他位置時，又有相應(yīng)的另一些Place cell激活.這使大腦能夠?qū)⑻囟ǖ奶卣餍畔⑴c相應(yīng)空間位置聯(lián)系起來，形成了空間位置記憶.但是單憑特征信息這一點卻不能對空間位置進行精確定位，就像如果我們只知道想去地方的樣子而不知道具體的地址，依然去不了想去的地方.而May-Britt Moser和Edvard I. Moser夫婦在大腦的內(nèi)嗅皮質(zhì)發(fā)現(xiàn)了大腦定位系統(tǒng)的另一關(guān)鍵組成細胞——“網(wǎng)格細胞”（Grid cell）.他們發(fā)現(xiàn)正是Grid cell將空間位置進行相應(yīng)的坐標標記，可以實現(xiàn)動物的精確定位及路徑尋找.所以當大腦擁有了Grid cell制定的坐標系統(tǒng)以及Place cell構(gòu)建的位置特征信息，就形成了相對完整的腦內(nèi)“地圖”，實現(xiàn)了內(nèi)置GPS的功能.這項研究不僅揭示了生物體空間位置記憶的神經(jīng)機制，也為人工智能及機器人的開發(fā)提供了理論基礎(chǔ).此外對一些與記憶相關(guān)的疾病，如阿爾茨海默病患者患病初期出現(xiàn)的迷路、無法辨識周邊環(huán)境等癥狀，利用大腦定位系統(tǒng)的機制也會幫助我們進一步了解這些患者空間記憶缺失的原理以及為治療疾病開發(fā)腦內(nèi)植入芯片提供空間.

1獲獎?wù)吆喗?/p>

1.1John O'Keefe

John O'Keefe（圖1），1939年11月18日出生于美國紐約，擁有美國和英國雙重國籍，現(xiàn)任英國倫敦學院大學（University College London，UCL）認知神經(jīng)科學研究所和解剖學系的教授.

John O'Keefe本科就讀于紐約城市學院，1963年獲學士學位.博士就讀于加拿大麥吉爾大學，攻讀生理心理學博士學位，導師為Ronald Melzaek教授.1967年他作為美國國立精神衛(wèi)生研究所博士后，在UCL和與Ronald Melzaek同為“疼痛門控學說”共同創(chuàng)立者的Patrick mall一起工作.他們的理論對后來許多諾貝爾獎級別的發(fā)現(xiàn)（內(nèi)啡膚）具有直接指導價值.1987年O'Keefe獲得UCL教授職位，從此再未離開過UCL，John O'Keefe不但發(fā)現(xiàn)了海馬體中的Place cell，并且進一步揭示了這類細胞以e相移的方式進行臨時編碼.2008年O'Keefe獲得美國格魯伯神經(jīng)學國際研究獎.2013年，John O'Keefe與May-Britt Moser和Edvard I. Moser分享了路易莎·格羅斯·霍維茨生物學或生物化學獎.

1.2May-Britt Moser及Edvard I. Moser夫婦

Edvard I. Moser（圖2），1962年4月27日出生于挪威奧勒松，現(xiàn)任挪威科技大學神經(jīng)科學和心理學教授，特隆赫姆系統(tǒng)神經(jīng)科學科維理研究所的主任.May-Britt Moser（圖2），1963年1月4日出生于挪威福斯納瓦格.現(xiàn)任挪威科技大學神經(jīng)科學教授，特隆赫姆系統(tǒng)神經(jīng)科學計算中心主任.

Moser夫婦本科及研究生均就讀于挪威奧斯陸大學，分別于1990年獲得學士學位、1995年獲得神經(jīng)生理學博士學位.1994至1996年Moser夫婦在愛丁堡大學神經(jīng)科學中心作博士后研究，并與John O'Keefe實驗室建立合作關(guān)系.之后夫婦二人一起回到挪威科技大學，被任命為心理生物學副教授.1998年Edvard I. Moser晉升為神經(jīng)科學和心理學正教授，2000年May-Britt Moser晉升為神經(jīng)科學正教授.2002年Moser夫婦共同建立了記憶生物學中心和Kavli研究所，致力于從神經(jīng)回路和系統(tǒng)水平上理解大腦功能，集中于空間記憶功能的研究.如前所述，Moser夫婦于2013年與John O'Keefe分享了路易莎·格羅斯·霍維茨生物學或生物化學獎.

2主要科學貢獻

位置感知和導航能力是大腦的基本功能.位置感知能力賦予人類認識環(huán)境中自身的位置以及其他物體的相對位置，而導航能力則是建立在前期運動和位置記憶之上，對距離及方向認知的整合，進行精確定位和路線查找.正是依靠這些空間位置記憶能力來認識及記錄周圍的環(huán)境，并繪制大腦內(nèi)的“認知地圖”.但是大腦中如何產(chǎn)生“認知地圖”？隨著Place cell及Grid cell的發(fā)現(xiàn)為我們逐步揭開了它的神秘機制.

2.1海馬區(qū)Place cell的發(fā)現(xiàn)

有關(guān)位置和導航的問題困擾了科學家很長時間.早在17世紀，歐洲經(jīng)驗主義者就認為人們對世界的認識起源于感官印象，可能是一種先驗的直覺.其中“空間概念（Space）”被提出，并認為其是思維中固有成分，人們通過空間感知世界.隨著實驗心理學以及神經(jīng)科學的發(fā)展，1948年，Edward Tolman在研究迷宮中運動的大鼠時，發(fā)現(xiàn)它們可以學會導航，并成功通過迷宮，猜想大腦一定是形成了一幅“認知地圖”.而隨后研究發(fā)現(xiàn)若將大鼠海馬損傷可導致其無法通過迷宮，并無法對環(huán)境中的改變產(chǎn)生響應(yīng).

為了更好的研究海馬在“認知地圖”中可能的作用，1971年John O'Keefe和Dostrovsky利用在體神經(jīng)電生理方法記錄了自由活動大鼠海馬體中神經(jīng)細胞的放電.他們首次在大鼠海馬CA1區(qū)發(fā)現(xiàn)一類獨特細胞.當大鼠運動到區(qū)域中某一特定位置可使這類神經(jīng)細胞放電；而在區(qū)域的其他位置，并不會引起這類細胞的放電，而這類細胞被稱為“Place cell”，引起“Place cell”放電的特定位置稱為Place field.John O'Keefe指出不同的Place field對應(yīng)于不同的Place cell放電，這樣海馬中很多不同的Place cell放電就形成了一幅所處環(huán)境的內(nèi)在地圖.

隨著John O'Keefe團隊的深入研究，他們發(fā)現(xiàn)Place cell還具有學習記憶的功能.研究指出當外界環(huán)境發(fā)生微小變化時，Place cell與Place field的對應(yīng)關(guān)系并不會發(fā)生明顯的改變，但是當環(huán)境發(fā)生很大變化時，Place cell與Place field的關(guān)系可以發(fā)生重新排列，或者對應(yīng)新的Place field，形成新的組合并能保持一定時間，這個過程稱作“Remapping”.因此，通過不同環(huán)境中對不同Place cell的激活，海馬可以構(gòu)造出很多地圖，也就是說大腦對環(huán)境的記憶是以不同Place cell組合方式儲存在海馬中.

John O'Keefe對海馬Place cell的發(fā)現(xiàn)開啟了人們對空間記憶的細胞學機制研究，此后不斷有研究發(fā)現(xiàn)與空間記憶相關(guān)的神經(jīng)元，包括邊界細胞（Boundary cell）、頭向細胞（Head direction cell）以及隨后即將介紹的網(wǎng)格細胞（Grid cell）.這些與空間記憶相關(guān)的細胞，相互聯(lián)系，共同形成大腦的空間定位系統(tǒng).

2.2內(nèi)嗅皮質(zhì)Grid cell的發(fā)現(xiàn)

繼Place cell的發(fā)現(xiàn)后長達30年的空間記憶神經(jīng)機制研究中，大多科學家更傾向于研究海馬內(nèi)神經(jīng)網(wǎng)絡(luò)的調(diào)節(jié)，直到Moser夫婦在內(nèi)嗅皮質(zhì)發(fā)現(xiàn)了Grid cell.其實早在Moser夫婦在O'Keefe實驗室做博士后研究的時候就提出，Place cell或是空間記憶的調(diào)節(jié)是否存在海馬區(qū)以外的機制.神經(jīng)解剖學研究發(fā)現(xiàn)，內(nèi)嗅皮質(zhì)的傳出纖維是海馬神經(jīng)傳入纖維的主要來源，并且大部分內(nèi)嗅皮質(zhì)的傳出纖維投射到海馬齒狀回及CA3區(qū)，經(jīng)過換元后可投射到背側(cè)海馬CA1區(qū)；此外也有部分內(nèi)嗅皮質(zhì)的傳出纖維可直接投射到CA1區(qū)，而CA1區(qū)正是Place cell所在區(qū)域.因此Morser夫婦對內(nèi)嗅皮質(zhì)神經(jīng)元放電與空間記憶功能進行了大量研究.

2005年，Moser夫婦首先在內(nèi)嗅皮質(zhì)記錄到一類與Place cell放電形式相似的細胞，這類細胞放電也表現(xiàn)出對特定位置的反應(yīng)性.但是與Place cell不同的是，它們的放電不依賴于外界的環(huán)境，而是在運動區(qū)域內(nèi)發(fā)生重復(fù)性規(guī)律放電，如果將每個放電區(qū)域作為一個節(jié)點，并將節(jié)點相連就會形成一種類似于蜂巢式的六邊形網(wǎng)格，而這種細胞就稱Grid cell.研究發(fā)現(xiàn)無論運動區(qū)域的大小及形狀變化，放電形成的網(wǎng)格總是布滿整個運動空間范圍，并且保持網(wǎng)格大小及結(jié)構(gòu)不變，而只改變網(wǎng)格的數(shù)目.此外研究也指出即使在黑暗情況下，大鼠Grid cell放電也可形成穩(wěn)定的網(wǎng)格.Moser夫婦的研究還指出不同內(nèi)嗅皮質(zhì)區(qū)域的Grid cell放電形成的網(wǎng)格大小不同，表現(xiàn)為內(nèi)嗅皮質(zhì)腹側(cè)的Grid cell放電形成網(wǎng)格大于中間層的Grid cell放電形成的網(wǎng)格.正是由于這些獨特且精確的網(wǎng)格放電模式賦予了Grid cell編碼空間環(huán)境及導航的能力.Grid cell網(wǎng)格放電結(jié)構(gòu)使得內(nèi)嗅皮質(zhì)與整個空間環(huán)境之間建立了穩(wěn)定而有效地靶向關(guān)系，且能保障在空間矢量關(guān)系上發(fā)生同步變化.

隨著研究的深入，Morser夫婦及John O'Keefe均指出Grid cell與之前發(fā)現(xiàn)的Place cell，Boundary cell和Head direction cell具有廣泛的功能聯(lián)系（Head direction cell的放電與動物頭部轉(zhuǎn)動的方向及角度有關(guān)；而當動物在封閉環(huán)境中碰到阻擋則會引起B(yǎng)ound-ary cell的放電）.其中Grid cell可整合Boundary cell，Head direction cell及視覺和本體感覺的距離信息，經(jīng)過分析不同內(nèi)嗅皮質(zhì)區(qū)域的Grid cell放電，并通過一些復(fù)雜的算法就可確定動物自身在這個六邊形網(wǎng)格中的精確坐標.此外，研究發(fā)現(xiàn)Grid cell，Boundary cell及Head direction cell均可投射到海馬Place cell，這些與空間位置相關(guān)的各類細胞相互影響，最終決定Place cell的放電形式.然而Grid cell雖然為空間位置找到了坐標系，但是如果想長期保存這樣的信息還需要大腦海馬區(qū)的記憶儲存功能配合，因此對Grid cell與Place cell交互作用的研究以及內(nèi)嗅皮質(zhì)與海馬體之間的環(huán)路對于完善空間記憶的研究也具有重要意義.

3科學意義

（1）該研究有助于人類認識人腦的高級功能，是實現(xiàn)從神經(jīng)元放電到認知功能聯(lián)系的典型模式.

盡管科學家在30年前就已經(jīng)弄清秀麗隱桿線蟲（Caenorhabditis elegans）302個神經(jīng)元之間的連接方式，但迄今為止，就連這種低級生物最基本的生存行為（如進食和交配）是如何產(chǎn)生的，也還不清楚.這中間所失的一環(huán)，就是神經(jīng)元活動和特定行為之間的關(guān)系.該研究在細胞層面共同實現(xiàn)大腦對位置和路徑的認知，成為這一領(lǐng)域研究的典型代表.

奧巴馬政府已于去年宣布啟動“腦計劃”（Brain Research through Advancing Innovative Neuroteehnologies，BRAIN），在2014年的啟動資金為1億多美元，致力于開發(fā)能記錄大群神經(jīng)元，甚至是整片腦區(qū)的電活動的新技術(shù).而在美國之外，全球還有很多其他大規(guī)模的腦科學項目.比如，歐盟的“人類大腦計劃”（The Human Brain Projeet），這一計劃為期十年，將耗資16億美元，致力于構(gòu)建能真正模擬人腦的超級計算機.盡管中國的腦科學研究與世界先進水平仍有差距，如能推動中國腦科學計劃的實施將會從整體上提高中國腦科學的研究水平.

（2）該研究有助于理解神經(jīng)精神疾病中腦回路異常的機制，對腦重大疾病的診斷和治療提供新的思路.

近年來隨著腦功能成像的發(fā)展，以及對神經(jīng)外科手術(shù)患者的研究均發(fā)現(xiàn)在人腦中存在Place cell和Grid cell，并且其放電形式及功能與動物研究一致，具有空間識別及記憶功能.

空間識別及記憶功能喪失是認知功能障礙性疾病的主要臨床表現(xiàn).如阿爾茨海默?。ˋlzheimer's disease，AD）患病初期就出現(xiàn)了迷路、無法辨識周邊環(huán)境等癥狀.2008年，John O'Keefe將對Place cell的研究推進到了更有實際意義的工作中，他發(fā)現(xiàn)在16個月Tg2576轉(zhuǎn)基因AD小鼠中，出現(xiàn)了明顯的Place cell空間識別功能障礙，表現(xiàn)為Place cell放電減少以及Place field增大，同時研究還指出Place cell的功能障礙程度與AD小鼠的認知行為以及海馬Ap斑塊的沉積密度高度相關(guān)，這提示對Place cell功能檢測可以敏感的反映AD小鼠認知功能及病理損傷程度，同時也可以成為AD療效評價的良好指標.

4諸多相關(guān)問題有待揭示

大腦“定位系統(tǒng)”的發(fā)現(xiàn)和研究已取得成果，隨之有很多相關(guān)問題有待進一步揭示.Morser夫婦及John O'Keefe均指出Grid cell與之前發(fā)現(xiàn)Place cell，Boundary cell和Head direction cell具有廣泛的功能聯(lián)系，對Grid cell與Place cell交互作用以及內(nèi)嗅皮質(zhì)與海馬之間的環(huán)路研究對于完善空間記憶的研究將具有重要意義.Grid cell在內(nèi)嗅皮質(zhì)被發(fā)現(xiàn)，而病理學研究指出在AD病理過程中最早受累的區(qū)域是內(nèi)嗅皮質(zhì)，那么內(nèi)嗅皮質(zhì)中Grid cell究竟對AD的早期癥狀的意義如何？另外，路徑導航方式在男性和女性之間有較大差別，男性擅長定向策略，而女性擅長路線策略，那么，大腦“定位系統(tǒng)”在男性和女性中是否也存在差異？對于“路癡”，是否也存在細胞水平的差別？這些差異是否可以通過后天學習與訓練而發(fā)生改變？

總之，John O'Keefe和Moser夫婦的研究工作為認知科學研究領(lǐng)域展現(xiàn)了一幅生動的有“跡”可循的藍圖，該研究成果對空間行為和空間探索的細胞學基礎(chǔ)進行揭示，對于破譯思想和行為背后的腦活動模式，甚至整個認知科學領(lǐng)域的發(fā)展都作出了巨大貢獻.

·高被引論文摘要·

被引頻次：11

大鼠多通道在體記錄

王一男，唐永強，潘璟瑋，等

多通道在體記錄技術(shù)，能在自由活動的動物腦內(nèi)，觀察和記錄局部腦區(qū)群體神經(jīng)元的活動狀況，是分析大腦神經(jīng)信息編碼的有力工具.要開展多通道在體記錄研究，多電極陣列驅(qū)動器的設(shè)計非常關(guān)鍵，也是實現(xiàn)該技術(shù)的一大難點根據(jù)轉(zhuǎn)動螺桿推動螺帽移動的機械驅(qū)動原理，作者設(shè)計了適合大鼠多通道在體記錄的、獨立可調(diào)式16道電極陣列驅(qū)動裝置.通過該裝置，可對16道記錄電極中的任意一道進行獨立驅(qū)動，從而控制每根記錄電極在大鼠大腦中的垂直記錄位置.運用該多電極陣列驅(qū)動裝置，對大鼠單側(cè)海馬腦區(qū)的多通道在體記錄表明：在大鼠海馬CA1區(qū)，存在不同放電波形和放電模式的神經(jīng)元，它們分別與海馬CA1區(qū)的錐體神經(jīng)元和中間神經(jīng)元相對應(yīng).一般錐體神經(jīng)元動作電位的放電波形較寬放電頻率則較低.在海馬CA1區(qū)還存在編碼空間環(huán)境中特定位置信息的神經(jīng)元，被稱為位置細胞.這些位置細胞在某一空間環(huán)境中有各自對應(yīng)的反應(yīng)區(qū)域在該區(qū)域內(nèi)，位置細胞的放電頻率增加，在區(qū)域外則基本維持在一較低的活動水平.

多通道在體記錄；大鼠；海馬；位置細胞

來源出版物：生物物理學報，2010，26（5）: 397-405

被引頻次：3

海馬位置細胞研究進展

高潔，隋建峰

摘要：位置細胞是與動物行為活動所處位置密切相關(guān)并具有復(fù)雜鋒電位的海馬錐體細胞，是腦內(nèi)認知地圖的基本組成單元.當個體處于特定的“位置野”時，相應(yīng)的位置細胞呈現(xiàn)最大放電.位置細胞并非單純的感覺神經(jīng)元，內(nèi)、外源性信息輸入均可影響位置細胞的放電活動，使位置野表現(xiàn)出一定的可塑性.本文對近年來關(guān)于海馬位置細胞的發(fā)現(xiàn)、分布及其電生理特性等研究進行了綜述.

關(guān)鍵詞：位置細胞；海馬；位置野

來源出版物：生理科學進展，2003，34（2）: 162-164

被引頻次：3

網(wǎng)格細胞在空間記憶中的作用

于平，徐暉，尹文娟，等

摘要：網(wǎng)格細胞存在于內(nèi)嗅皮層，具有顯著的空間放電特征，并呈現(xiàn)出網(wǎng)格圖樣的放電結(jié)構(gòu).近年來網(wǎng)格細胞的發(fā)現(xiàn)及其功能研究，為深入闡釋空間記憶的神經(jīng)機制開辟了新的視角.本文詳細介紹了網(wǎng)格細胞的發(fā)現(xiàn)、神經(jīng)解剖學聯(lián)系及空間放電特征；通過網(wǎng)格細胞與位置細胞的對比分析，闡釋網(wǎng)格細胞利用自身運動信息進行空間編碼的機制，以及在空間記憶中所發(fā)揮的路徑整合器功能.

關(guān)鍵詞：網(wǎng)格細胞；位置細胞；空間記憶；路徑整合

來源出版物：心理科學進展，2009，17（6）: 1228-1233聯(lián)系郵箱：于萍，yupingyp@gmail.com

被引頻次：2

記憶過程中海馬CA1區(qū)神經(jīng)元的集群放電特征

于萍，袁水霞，李霞，等

摘要：觀察空間工作記憶過程中海馬CA1區(qū)神經(jīng)元群的放電特征.應(yīng)用多通道神經(jīng)元集群放電記錄技術(shù)，同步觀察和記錄清醒大鼠在執(zhí)行延遲選擇任務(wù)時的行為軌跡以及海馬CA1區(qū)神經(jīng)元的放電活動.發(fā)現(xiàn)：海馬CA1區(qū)位置細胞的位置野是在學習過程中逐漸形成并可消退；部分位置細胞的放電對未來目標定向性行為具有預(yù)測作用；在空間工作記憶過程中，神經(jīng)元放電之間的相關(guān)性加強，神經(jīng)元之間以及神經(jīng)元與局部場電位之間存在相位編碼方式.結(jié)果提示海馬CA1區(qū)神經(jīng)元參與對空間信息的初級編碼和加工，并為未來行為決策提供有效信息，而且海馬對信息的加工是通過局部神經(jīng)網(wǎng)絡(luò)進行，時間編碼可能是海馬信息加工的重要方式之一.

關(guān)鍵詞：空間工作記憶；海馬；位置細胞；位置野；多通道記錄

來源出版物：心理學報，2011，43（8）: 917-928聯(lián)系郵箱：郭春彥，guocy@mail.cnu.edu.cn

被引頻次：1

海馬位置細胞對空間信息的處理

左艷芳，羅非，崔彩蓮

摘要：海馬位置細胞接收各種來源的空間信息后，可對這些信息進行加工處理，在海馬內(nèi)形成認知地圖或加強聯(lián)合皮層內(nèi)細胞集群的突觸聯(lián)系以形成對空間位置的永久記憶.海馬內(nèi)的空間信息輸出后，在伏核（nucleus accumbens，NAC）內(nèi)與其它來源的信息進行整合，最終通過運動環(huán)路形成目標指向性行為.

關(guān)鍵詞：位置細胞；海馬；位置野；位置線索；認知地圖

來源出版物：生理科學進展，2006，37（1）: 6-10

被引頻次：1

海馬位置細胞空間信息處理機制的研究進展

胡波，隋建峰

摘要：位置細胞是具有位置特異性和復(fù)雜鋒電位的海馬錐體細胞.三十多年來，人們致力于研究位置細胞放電與空間信息處理之間的關(guān)系，并取得了可喜的進展.但遺憾的是，位置細胞處理空間信息的詳細機制至今仍不清楚.本文就近年來關(guān)于海馬位置細胞空間信息處理機制的研究進展做一綜述.

關(guān)鍵詞：海馬；位置細胞；位置野；放電

來源出版物：中華神經(jīng)醫(yī)學雜志，2005，4（4）: 416-418

被引頻次：353

來源出版物：Journal of Neuroscience，1996，16（6）: 2112-2126

被引頻次：302

Place cells, Head Direction cells, and the learning of landmark stability

Knierim，JJ； Kudrimoti，HS； Mcnaughton，BL

Abstract： Previous studies have shown that hippocampal place fields are controlled by the salient sensory cues in the environment，in that rotation of the cues causes an equal rotation of the place fields. We trained rats to forage for food pellets in a gray cylinder with a single salient directional cue，a white card covering 90 degrees of the cylinder wall. Half of the rats were disoriented before being placed in the cylinder，in order to disrupt their internal sense of direction. The other half were not disoriented before being placed in the cylinder； for these rats，there was presumably a consistent relationship between the cue card and their internal direction sense. We subsequently recorded hippocampal place cells and thalamic head direction cells from both groups of rats as they moved in the cylinder； between some sessions the cylinder and cue card were rotated to a new direction. All rats were disoriented before recording. Under these conditions，the cue card had much weaker control over the place fields and head direction cells in the rats that had been disoriented during training than in the rats that had not been disoriented. For the former group，the place fields often rotated relative to the cue card or completely changed their firingproperties between sessions，In all recording sessions，the head direction cells and place cells were strongly coupled. It appears that the strength of cue control over place cells and head direction cells depends on the rat's learned perception of the stability of the cues.

Keywords： place cells； head direction cells； landmark learning； path integration； hippocampus； direction sense； spatial learning

來源出版物：Journal of Neuroscience，1995，15（3）: 1648-1659

被引頻次：280

Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry

Brun，VH； Otnaess，MK； Molden，S； et al.

Abstract： Place cells in hippocampal area CA1 may receive positional information from the intrahippocampal associative network in area CA3 or directly from the entorhinal cortex. To determine whether direct entorhinal connections support spatial ring and spatial memory，we removed all input from areas CA3 to CA1，thus isolating the CA1 area. Pyramidal cells in the isolated CA1 area developed sharp and stable place fields. Rats with an isolated CA1 area showed normal acquisition of an associative hippocampal-dependent spatial recognition task. Spatial recall was impaired. These results suggest that the hippocampus contains two functionally separable memory circuits: The direct entorhinal-CA1 system is sufficient for recollection-based recognition memory，but recall depends on intact CA3-CA1 connectivity.

Keywords： pyramidal cells； spatial memory； goal location； unit-activity； rats； cortex； fields； model； Acid； CA3

來源出版物：Science，2002，296（5576）: 2243-2246

被引頻次：247

Head-direction cells in the rat posterior cortex. 1. anatomical distribution and behavioral modulation

Chen，LL； Lin，LH； Green，EJ； et al.

Abstract： We examined the behavioral modulation of head-directional information processing in neurons of the rat posterior cortices，including the medial prestriate（area Oc2M）and retrosplenial cortex（areas RSA and RSG）. Single neurons were recorded in freely moving rats which were trained to perform a spatial working memory task on a radial-arm maze in a cue-controlled room. A dual-light-emitting diode（dual-LED）recording headstage，mounted on the animals' heads，was used to track head position and orientation. Planar modes of motion，such as turns，straight motion，and nonlocomotive slates，were categorized using an objective scheme based upon the differential contributions of movement parameters，including linear and angular velocity of the head. Of 662 neurons recorded from the posterior cortices，41 head-direction（HD）cells were identified based on the criterion of maintained directional bias in the absence of visual cues or in the dark. HD cells constituted 7 of 257（2.7%）cells recorded in Oc2M，26 of 311（8.4%）cells in RSA，and 8 of 94（8.5%）cells in RSG. Spatial tuning of HD cell firing was modulated by the animal's behaviors in some neurons. The behavioral modulation occurred either at the preferred direction or at all directions. Moreover，the behavioral selectivity was more robust for turns than straight motions，suggesting that the angular movements may significantly contribute to the head-directional processing. These behaviorally selective HD cells were observed most frequently in Oc2M（4/7，57%），as only 5 of 26（19%）of RSA cells and none of the RSG cells showed behavioral modulation. These data，taken together with the anatomical evidence for a cascade of projections from Oc2M to RSA and thence to RSG，suggest that there may be a simple association between movement and head-directionality that serves to transform the egocentric movement representation in the neocortex into an allocentric directional representation in the periallocortex.

Keywords： single units； head direction； behavior； neocortex； retrosplenial cortex

來源出版物：Experimental Brain Research，1994，101（1）: 8-23

被引頻次：242

Head direction cells and the neurophysiological basis for a sense of direction

Taube，JS

Abstract： Animals require two types of fundamental information for accurate navigation: location and directional heading. Current theories hypothesize that animals maintain a neural representation，or cognitive map，of external space in the brain. Whereas cells in the rat hippocampus and parahippocampal regions encode information about location，a second type of allocentric spatial cell encodes information about the animal's directional heading，independent of the animal's on-going behaviors. These head direction（HD）cells are found in several areas of the classic Papez circuit. This review focuses on experimental studies conducted on HD cells and describes their discharge properties，functional significance，role in path integration，and responses to different environmental manipulations. The anterior dorsal thalamic nucleus appears critical for the generation of the directional signal. Both motor and vestibular cues also play important roles in the signal's processing. The neural network models proposed to account for HD cell firing are compared with known empirical findings. Examples from clinical cases of patients with topographical disorientation are also discussed. It is concluded that studying the neural mechanisms underlying the HD signal provides an excellent opportunity for understanding how the mammalian nervous system processes a high level cognitive signal.

Keywords： freely-moving rats； hippocampal place cells； anterior thalamic nuclei； single unit-activity； complex-spike cells； pure topographical disorientation； monkeys macaca-fascicularis； posterior cingulate cortex； dorsal tegmental nucleus； spatial memory

來源出版物：Progress in Neurobiology，1998，55（3）: 225-256聯(lián)系郵箱：Taube，JS； jeffrey.taube@dartmouth.edu

被引頻次：153

Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus

Rotenberg，A； Mayford，M； Hawkins，RD； et al.

Abstract： To relate different forms of synaptic plasticity to the formation and maintenance of place cells in the hippocampus，we have recorded place cells in freely behaving，transgenic mice that express a mutated Ca2+-independent form of CaM Kinase II. These mice have normal long-term potentiation（LTP）at 100 Hz，but they lack LTP in response to stimulation at 5-10 Hz and are impaired on spatial memory tasks. In these transgenic mice，the place cells in the CA1 region have three important differences from those of wild types: they are less common，less precise，and less stable. These findings suggest that LTP in the 5-10 Hz range may be important for the maintenance of place-field stability and that this stability may be essential for the storage of spatial memory.

Keywords： spatial firing patterns； freely-behaving rats； complex-spike cells； moving rats； environment； units

來源出版物：Cell，1996，87（7）: 1351-1361

被引頻次：136

Spatial view cells and the representation of place in the primate hippocampus

Rolls，ET

Abstract： The information represented in the primate hippocampus is being analysed by making recordings in monkeys actively walking in the laboratory. In a sample of 352 cells recorded in this situation，no "place" cells have so far been found. Instead，we have found a considerable population of "spatial view" cells tuned to respond when the monkey looks at small parts of the environment. We have been able to demonstrate（1）that these hippocampal neurons respond to a view of space "out there，" not to the place where the monkey is；（2）that the responses depend on where the monkey is looking，by measuring eye position；（3）that the responses in some cases（e.g.，CA1 but not CA3）still occur if the view details are obscured with curtains；（4）that the cells（in，e.g.，CA1）retain part of their "space" tuning even in complete darkness，for several minutes； and（5）that the spatial representation is allocentric. The spatial representation is，thus，different from that in the rat hippocampus，in which place cells respond based on where the rat is located. The representation is also different from that described in the parietal cortex，where neurons respond in egocentric coordinates. This representation of space "out there" provided by primate spatial view cells would be an appropriate part of a memory system involved in memories of particular events or episodes，for example，of where in an environment an object was seen. Spatial view cells（in conjunction with whole body motion cells in the primate hippocampus，and head direction cells in the primate presubiculum）would also be useful as part of a spatial navigation system，for which they would provide a memory component.

Keywords： hippocampus； spatial view cells； place cells； episodic memory； allocentric coordinate system； memory

來源出版物：Hippocampus，1999，9（4）: 464-480聯(lián)系郵箱：Rolls，ET； Edmund.Rolls@psy.ox.ac.uk

被引頻次：92

Head Direction cell-activity monitored in a novel environment and during a cue conflict situation

Taube，JS； Burton，HL

Abstract： 1. Recent conceptualizations of the neural systems used during navigation have classified two types of sensory information used by animals: landmark cues and internally based（idiothetic； e.g.，vestibular，kinesthetic）sensory cues. Previous studies have identified neurons in the postsubiculum and the anterior thalamic nuclei that discharge as a function of the animal's head direction in the horizontal plane. The present study was designed to determine how animals use head direction（HD）cells for spatial orientation and the types of sensory cues involved. 2. HD cell activity was monitored in the postsubiculum and anterior thalamic nucleus of rats in a dual-chamber apparatus in an experiment that consisted of two phases. In the first phase，HD cell activity was monitored as an animal moved from a familiar environment to a novel environment. It was hypothesized that if HD cells were capable of using idiothetic sensory information，then the direction of maximal discharge should remain relatively unchanged as the animal moved into an environment where it was unfamiliar with the landmark cues. In the second phase，HD cells were monitored under conditions in which a conflict situation was introduced between the established landmark cues and the animal's internally generated sensory cues. 3. HD cells were initially recorded in a cylinder containing a single orientation cue（familiar environment）. A door was then opened，and the rat entered a U-shaped passageway leading to a rectangular chamber containing a different prominent cue（novel environment）. For most HD cells，the preferred direction remained relatively constant between the cylinder and passageway/rectangle，although many cells showed a small（6-30 degrees）shift intheir preferred direction in the novel environment. This directional shift was maintained across different episodes in the passageway/rectangle. 4. Before the next session，the orientation cue in the cylinder was rotated 90 degrees，and the animal returned to the cylinder. The cell's preferred direction usually shifted between 45 and 90 degrees in the same direction. 5. The rat was then permitted to walk back through the passageway into the now-familiar rectangle. Immediately upon entering the passageway，the preferred direction returned to its original（prerotation）orientation and remained at this value while the rat was in the rectangle. When the rat was allowed to walk back into the cylinder，one of three outcomes occurred: 1）the cell's preferred direction shifted，such that it remained linked to the cylinder's rotated cue card； 2）the cell's preferred direction remained unchanged from its orientation in the rectangle； or 3）the cell's preferred direction shifted to a new value that lay between the preferred directions for the rotated cylinder condition and rectangle. 6. There was little change in the HD cell's background firing rate，peak firing rate，or directional firing range for both the novel and cue-conflict situations. 7. Simultaneous recordings from multiple cells in different sessions showed that the preferred directions remained ''in register'' with one another. Thus，when one HD cell shifted its preferred direction a specific amount，the other HD cell also shifted its preferred direction the same amount. 8. Results across different series within the same animal showed that the amount the preferred direction shifted in the first Novel series was about the same amount as the shifts observed in subsequent Novel series. In contrast，as the animal experienced more Conflict series，HD cells tended to use the cylinder's cue card less as an orientation cue when the animal returned to the rotated cylinder condition from the rectangle. 9. These results suggest that HD cells in the postsubiculum and anterior thalamic nuclei receive information from both landmark and idiothetic sensory cues，and when both types of cues are available，HD cells preferentially use the landmark cues as long as they are perceived as stable.

Keywords： freely-moving rats； path integration； mamillary body； place units； postsubiculum； cortex； task； projections； navigation； complex來源出版物：Journal of Neurophysiology，1995，74（5）: 1953-1971

被引頻次：92

Place cells, navigational accuracy, and the human hippocampus

O'Keefe，J； Burgess，N； Donnett，JG； et al

Abstract： The hippocampal formation in both rats and humans is involved in spatial navigation. In the rat，cells coding for places，directions，and speed of movement have been recorded from the hippocampus proper and/or the neighbouring subicular complex. Place fields of a group of the hippocampal pyramidal cells cover the surface of an environment but do not appear to do so in any systematic fashion. That is，there is no topographical relation between the anatomical location of the cells within the hippocampus and the place fields of these cells in an environment. Recent work shows chat place cells are responding to the summation of two or more Gaussian curves，each of which is fixed at a given distance to two or more walls in the environment. The walls themselves are probably identified by their allocentric direction relative to the rat and this information may be provided by the head direction cells. The right human hippocampus retains its role in spatial mapping as demonstrated by its activation during accurate navigation in imagined and virtual reality environments. In addition，it may have taken on wider memory functions，perhaps by the incorporation of a linear time tag which allows for the storage of the times of visits to particular locations. This extended system would serve as the basis for a spatio-temporal event or episodic memory system.

Keywords： hippocampus； spatial navigation； rat； virtual reality； functional imaging； neural network

來源出版物：Philosophical Transactions of The Royal Society of London Series B-Biological Sciences，1998，353（1373）: 1333-1340

被引頻次：78

Entorhinal cortex grid cells can map to hippocampal place cells by competitive learning

Rolls，Edmund T.； Stringer，Simon M.； Elliot，Thomas

Abstract： 'Grid cells' in the dorsocaudal medial entorhinal cortex（dMEC）are activated when a rat is located at any of the vertices of a grid of equilateral triangles covering the environment. dMEC grid cells have different frequencies and phase offsets. However，cells in the dentate gyrus（DG）and hippocampal area CA3 of the rodent typically display place fields，where individual cells are active over only a single portion of the space. In a model of the hippocampus，we have shown that the connectivity from the entorhinal cortex to the dentate granule cells could allow the dentate granule cells to operate as a competitive network to recode their inputs to produce sparse orthogonal representations，and this includes spatial pattern separation. In this paper we show that the same computational hypothesis can account for the mapping of EC grid cells to dentate place cells. We show that the learning in the competitive network is an important part of the way in which the mapping can be achieved. We further show that incorporation of a short term memory trace into the associative learning can help to produce the relatively broad place fields found in the hippocampus.

Keywords： entorhinal cortex； grid cell； place cell； competitive network； hippocampus； dentate gyrus

來源出版物：Network-Computation In Neural Systems，2006，17（4）: 447-465聯(lián)系郵箱：Elliot，Thomas； Edmund.Rolls@psy.ox.ac.uk

·推薦論文摘要·

解碼大腦的空間方位認知

馬曉宇，林龍年

摘要：在過去的幾十年間，與大腦空間方位認知功能相關(guān)的位置細胞、網(wǎng)格細胞、頭朝向細胞和邊界細胞陸續(xù)被發(fā)現(xiàn)，它們共同構(gòu)成了大腦內(nèi)部的導航定位系統(tǒng).O'Keefe教授和Moser夫婦這三位科學家也正是由于發(fā)現(xiàn)了位置細胞和網(wǎng)格細胞，而共同獲得了2014年的諾貝爾生理學或醫(yī)學獎.

關(guān)鍵詞：空間方位認知；海馬；位置細胞；內(nèi)嗅皮層；網(wǎng)格細胞

來源出版物：生命科學，2014，26（12）: 1248-1254

多通道在體記錄技術(shù)——神經(jīng)元放電與節(jié)律性場電位間的相位分析方法

王策群，陳強，張櫨，等

摘要：本文旨在介紹神經(jīng)元放電序列與節(jié)律性場電位間的相位分析方法.多通道在體記錄技術(shù)能同時記錄群體神經(jīng)元和局部場電位的活動信號.神經(jīng)元的放電活動一般表征為放電時間序列；而在局部場電位信號中，則包含有不同頻率成分的周期性節(jié)律振蕩.相位分析主要考察神經(jīng)元放電時刻與周期性節(jié)律場電位相位間的相互關(guān)系.具體分析時，先運用Hilbert變換計算出某一頻段節(jié)律場電位信號的瞬時相位值，然后再計算某一神經(jīng)元放電序列中每個動作電位相對于該節(jié)律場電位的放電相位，最后通過考察這些放電相位的分布特性，來判斷該神經(jīng)元與該節(jié)律場電位相位間的放電相位關(guān)系.如一神經(jīng)元放電序列對某種節(jié)律場電位的相位分布經(jīng)統(tǒng)計檢驗不是隨機的，則表明該神經(jīng)元對這種節(jié)律場電位有放電鎖相關(guān)系.Theta相位進動則是一種特殊的神經(jīng)元放電與周期性節(jié)律場電位間的相位關(guān)系，也是海馬位置細胞放電的基本特性之一.海馬位置細胞在位置野內(nèi)一般呈theta節(jié)律簇狀放電模式，而相位進動是指每一theta波內(nèi)放電的theta相位，相對上一theta波會逐漸提前.這一現(xiàn)象可通過對位置細胞放電的theta相位和動物實時位置使用線性模型來描述；并運用圓周線性相關(guān)分析法，計算它們之間的相關(guān)系數(shù)，從而研究位置細胞在位置野中的放電相對于theta相位的進動情況.通過相位分析，可以幫助我們了解神經(jīng)元放電與節(jié)律性場電位信號間的時間信息編碼特性.

關(guān)鍵詞：多通道在體記錄；放電鎖相；位置細胞；相位進動

來源出版物：生理學報，2014，66（6）:746-755聯(lián)系郵箱：林龍年，lnlin@brain.ecnu.edu.cn

大鼠海馬結(jié)構(gòu)CA1位置細胞對感覺錯配適應(yīng)的相關(guān)反應(yīng)

鄒丹，吳敏范，金戈，等

摘要：目的：觀察大鼠經(jīng)過學習其海馬結(jié)構(gòu)接受視覺-前庭-本體感覺錯配格局并將其視為匹配的狀態(tài)后CA1位置細胞的電活動，為揭示海馬結(jié)構(gòu)可編碼感覺輸入的任何組合提供依據(jù).方法：應(yīng)用微電極細胞外記錄方法，記錄清醒大鼠在適應(yīng)視覺-前庭-本體感覺錯配條件后海馬結(jié)構(gòu)CA1位置細胞神經(jīng)元放電情況.結(jié)果：56個位置細胞中，29個神經(jīng)元在正向狀態(tài)中有顯著的空間放電（正向相關(guān)神經(jīng)元），19個神經(jīng)元在反向狀態(tài)中有顯著的空間放電（反向相關(guān)神經(jīng)元）.位置野內(nèi)放電頻率的分布呈現(xiàn)不對稱及負偏斜.結(jié)論：大鼠海馬結(jié)構(gòu)位置細胞可編碼不能自然發(fā)生的新的感覺輸入配置，更新海馬結(jié)構(gòu)比較器內(nèi)的信息.

關(guān)鍵詞：感覺錯配；海馬；位置細胞；神經(jīng)元放電

來源出版物：中國醫(yī)科大學學報，2014，43（2）: 146-149聯(lián)系郵箱：鄒丹，zoudan1166@hotmail.com

視覺-前庭感覺-本體感覺錯配適應(yīng)大鼠海馬CA1區(qū)位置細胞的放電特征

鄒丹，金戈，符文雙

摘要：目的：觀察大鼠經(jīng)過學習其海馬結(jié)構(gòu)接受視覺-前庭感覺-本體感覺錯配格局并將其視為匹配的狀態(tài)后 CA1區(qū)位置細胞的電活動，為揭示海馬結(jié)構(gòu)可編碼感覺輸入的任何組合提供依據(jù).方法：建立視覺-前庭感覺-本體感覺錯配格，根據(jù)對海馬結(jié)構(gòu)齒狀回 θ節(jié)律的記錄及其電功率的計算，獲知大鼠適應(yīng)該感覺沖突后，應(yīng)用鎢絲微電極細胞外記錄方法，記錄清醒大鼠在適應(yīng)視覺-前庭感覺-本體感覺錯配條件后海馬 CA1區(qū)位置細胞神經(jīng)元集群放電情況.結(jié)果：56個位置細胞中，14個（25.0%）神經(jīng)元在感覺正配及錯配條件下均有位置穩(wěn)定的空間放電（雙向移動相關(guān)經(jīng)驗非依賴神經(jīng)元），33個（58.9%）神經(jīng)元在感覺正配及錯配條件下依次出現(xiàn)位置不穩(wěn)的空間放電（雙向移動相關(guān)經(jīng)驗依賴神經(jīng)元）.經(jīng)驗非依賴神經(jīng)元的位置野長度及非對稱指數(shù)的均值大于經(jīng)驗依賴型神經(jīng)元，差異有統(tǒng)計學意義（P＜0.01，P＜0.05）.此外，位置野內(nèi)放電頻率的分布呈現(xiàn)出不對稱及負偏斜.結(jié)論：動物在適應(yīng)自然情況下不可能出現(xiàn)的新的感覺配置后，海馬結(jié)構(gòu)能編碼這一配置并能更新其儲存的記憶，接受新的配置作為匹配狀態(tài).海馬結(jié)構(gòu)可能編碼感覺輸入的任何組合.

關(guān)鍵詞：感覺錯配；適應(yīng)；海馬；位置細胞；神經(jīng)元放電

來源出版物：第二軍醫(yī)大學學報，2014，35（6）: 592-597聯(lián)系郵箱：鄒丹，zoudan1166@hotmail.com

Coherence among Head Direction Cells before Eye Opening in Rat Pups

Bjerknes，Tale L.； Langston，Rosamund F； Kruge，Ingvild U.； et al.

Abstract： Mammalian navigation is thought to depend on an internal map of space consisting of functionally specialized cells in the hippocampus and the surrounding parahippocampal cortices ［1-7］. Basic properties of this map are present when rat pups explore the world outside of their nest for the first time，around postnatal day 16-18（P16-P18）［810］. One of the first functions to be expressed in navigating animals is the directional tuning of the head direction cells ［8，9］. To determine whether head direction tuning is expressed at even earlier ages，before the start of exploration，and to establish whether vision is necessary for the development of directional tuning，we recorded neural activity in pre- and parasubiculum，or medial entorhinal cortex，from P11 onward，3-4 days before the eyelids unseal. Head direction cells were present from the first day of recording. Firing rates were lower than in adults，and preferred firing directions were less stable，drifting within trials and changing completely between trials. Yet the cells drifted coherently，i.e.，relative firing directions were maintained from one trial to the next. Directional tuning stabilized shortly after eye opening. The data point to a hardwired attractor network for representation of head direction in which directional tuning develops before vision and visual input serves primarily to anchor firing direction to the external world.

Keywords： freely moving rats； geometric borders； entorhinal cortex； vestibular input； spatial map； representation； postsubiculum； system

來源出版物：Current Biology，2015，25（1）: 103-108聯(lián)系郵箱：Moser，MB； maybm@ntnu.no

Shearing-induced asymmetry in entorhinal grid cells

Stensola，Tor； Stensola，Hanne； Moser，May-Britt； et al.

Abstract： Grid cells are neurons with periodic spatial receptive fields（grids）that tile two-dimensional space in a hexagonal pattern. To provide useful information about location，grids must be stably anchored to an external reference frame. The mechanisms underlying this anchoring process have remained elusive. Here we show in differently sized familiar square enclosures that the axes of the grids are offset from the walls by an angle that minimizes symmetry with the borders of the environment. This rotational offset is invariably accompanied by an elliptic distortion of the grid pattern. Reversing the ellipticity analytically by a shearing transformation removes the angular offset. This，together with the near-absence of rotation in novel environments，suggests that the rotation emerges through non-coaxial strain as a function of experience. The systematic relationship between rotation and distortion of the grid pattern points to shear forces arising from anchoring to specific geometric reference points as key elements of the mechanism for alignment of grid patterns to the external world.

來源出版物：Nature，2015，518（7538）: 207-212

Grid cell symmetry is shaped by environmental geometry

Krupic，Julija； Bauza，Marius； Burton，Stephen； et al.

Abstract： Grid cells represent an animal's location by firing in multiple fields arranged in a striking hexagonal array. Such an impressive and constant regularity prompted suggestions that grid cells represent a universal and environmental-invariant metric for navigation. Originally the properties of grid patterns were believed to be independent of the shape of the environment and this notion has dominated almost all theoretical grid cell models. However，several studies indicate that environmental boundaries influence grid firing，though the strength，nature and longevity of this effect is unclear. Here we show that grid orientation，scale，symmetry and homogeneity are strongly and permanently affected by environmental geometry. We found that grid patterns orient to the walls of polarized enclosures such as squares，but not circles. Furthermore，the hexagonal grid symmetry is permanently broken in highly polarized environments such as trapezoids，the pattern being more elliptical and less homogeneous. Our results provide compelling evidence for the idea that environmental boundaries compete with the internal organization of the grid cell system to drive grid firing. Notably，grid cell activity is more local than previously thought and as a consequence cannot provide a universal spatial metric in all environments.

來源出版物：Nature，2015，518（7538）: 232-237

Grid cells and cortical representation

Moser，Edvard I.； Roudi，Yasser； Witter，Menno P.； et al.

Abstract： One of the grand challenges in neuroscience is to comprehend neural computation in the association cortices，the parts of the cortex that have shown the largest expansion and differentiation during mammalian evolution and that are thought to contribute profoundly to the emergence of advanced cognition in humans. In this Review，we use grid cells in the medial entorhinal cortex as a gateway to understand network computation at a stage of cortical processing in which firing patterns are shaped not primarily by incoming sensory signals but to a large extent by the intrinsic properties of the local circuit.

Keywords： medial entorhinal cortex； hippocampal place cells； primary visual-cortex； monkey striate cortex； freely-moving rat； human spatial navigation； neurons in-vitro； path-integration； receptive-fields； orientation selectivity

來源出版物：Nature Reviews Neuroscience，2014，15（7）: 466-481聯(lián)系郵箱：Moser，Edvard I； edvard.moser@ntnu.no

Functional connectivity of the entorhinal-hippocampal space circuit

Zhang，Sheng-Jia； Ye，Jing ； Couey，Jonathan J.； et al.

Abstract： The mammalian space circuit is known to contain several functionally specialized cell types，such as place cells in the hippocampus and grid cells，head-direction cells and border cells in the medial entorhinal cortex（MEC）. The interaction between the entorhinal and hippocampal spatial representations is poorly understood，however. We have developed an optogenetic strategy to identify functionally defined cell types in the MEC that project directly to the hippocampus. By expressing channelrhodopsin-2（ChR2）selectively in the hippocampus-projecting subset of entorhinal projection neurons，we were able to use light-evoked discharge as an instrument to determine whether specific entorhinal cell groups-such as grid cells，border cells and head-direction cells-have direct hippocampal projections. Photoinduced firing was observed at fixed minimal latencies in all functional cell categories，with grid cells as the most abundant hippocampus-projecting spatial cell type. We discuss how photoexcitation experiments can be used to distinguish the subset of hippocampus-projecting entorhinal neurons from neurons that are activated indirectly through the network. The functional breadth of entorhinal input implied by this analysis opens up the potential for rich dynamic interactions between place cells in the hippocampus and different functional cell types in the entorhinal cortex（EC）.

signals but to a large extent by the intrinsic properties of the local circuit.

Keywords： hippocampus； entorhinal cortex； grid cells； border cells； place cells； optogenetics

來源出版物：Philosophical Transactions of the Royal Society B-Biological Sciences，2014，369（1635）文獻號：20120516

聯(lián)系郵箱：Moser，MB； maybm@ntnu.no

Optogenetic dissection of entorhinal-hippocampal functional connectivity

Zhang SJ； Ye J； Miao C； et al.

Abstract： We used a combined optogenetic-electrophysiological strategy to determine the functional identity of entorhinal cells with output to the place-cell population in the hippocampus. Channelrhodopsin-2（ChR2）was expressed selectively in the hippocampus-targeting subset of entorhinal projection neurons by infusing retrogradely transportable ChR2-coding recombinant adeno-associated virus in the hippocampus. Virally transduced ChR2-expressing cells were identified in medial entorhinal cortex as cells that fired at fixed minimal latencies in response to local flashes of light. A large number of responsive cells were grid cells，but short-latency firing was also induced in border cells and head-direction cells，as well as cells with irregular or nonspatial firing correlates，which suggests that place fields may be generated by convergence of signals from a broad spectrum of entorhinal functional cell types.

Keywords： hippocampus； entorhinal cortex； grid cells； border cells； place cells； optogenetics

來源出版物：Science，2013，340（6128）: 273

The 2014 Nobel Prize in Physiology or Medicine： A Spatial Model for Cognitive Neuroscience

Burgess，Neil

Abstract： Understanding how the cognitive functions of the brain arise from its basic physiological components has been an enticing final frontier in science for thousands of years. The Nobel Prize in Physiology or Medicine 2014 was awarded one half to John O'Keefe，the other half jointly to May-Britt Moser and Edvard I. Moser "for their discoveries of cells that constitute a positioning system in the brain.'' This prize recognizes both a paradigm shift in the study of cognitive neuroscience，and some of the amazing insights that have followed from it concerning how the world is represented within the brain.

Keywords： freely-moving rat； hippocampal place units； entorhinal cortex； head-direction； grid cells； memory； map； representation；environment； ensemble

來源出版物：Neuron，2014，84（6）: 1120-1125聯(lián)系郵箱：Burgess，Neil； n.burgess@ucl.ac.uk

Pyramidal and Stellate Cell Specificity of Grid and Border Representations in Layer 2 of Medial Entorhinal Cortex

Tang，Qiusong； Burgalossi，Andrea； Ebbesen，Christian Laut

Abstract： In medial entorhinal cortex，layer 2 principal cells divide into pyramidal neurons（mostly calbindin positive）and dentate gyrus-projecting stellate cells（mostly calbindin negative）. We juxtacellularly labeled layer 2 neurons in freely moving animals，but small sample size prevented establishing unequivocal structure-function relationships. We show，however，that spike locking to theta oscillations allows assigning unidentified extracellular recordings to pyramidal and stellate cells with similar to 83% and similar to 89% specificity，respectively. In pooled anatomically identified and theta-locking-assigned recordings，nonspatial discharges dominated，and weakly hexagonal spatial discharges and head-direction selectivity were observed in both cell types. Clear grid discharges were rare and mostly classified as pyramids（19%，19/99 putative pyramids versus 3%，3/94 putative stellates）. Most border cells were classified as stellate（11%，10/94 putative stellates versus 1%，1/99 putative pyramids）. Our data suggest weakly theta-locked stellate border cells provide spatial input to dentate gyrus，whereas strongly theta-locked grid discharges occur mainly in hexagonally arranged pyramidal cell patches and do notfeed into dentate gyrus.

Keywords： freely moving rats； spatial representations； geometric borders； neurons； interneurons； organization； modulation； mouse

來源出版物：Neuron，2014，84（6）: 1191-1197

Medial Entorhinal Cortex Lesions Only Partially Disrupt Hippocampal Place Cells and Hippocapus-Dependent Place Memory

Hales，Jena B.； Schlesiger，Magdalene I.； Leutgeb，Jill K.； et al.

Abstract： The entorhinal cortex provides the primary cortical projections to the hippocampus，a brain structure critical for memory. However，it remains unclear how the precise firing patterns of medial entorhinal cortex（MEC）cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields，but with decreased spatial precision and decreased long-term spatial stability. In addition，MEC rats were as impaired in the water maze as hippocampus rats，while rats with combined MEC and hippocampal lesions had an even greater deficit. However，MEC rats were not impaired on other hippocampus-dependent tasks，including those in which an object location or context was remembered. Thus，the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory，but it is necessary for the normal acquisition of place memory.

Keywords： spatial memory； recognition memory； dentate gyrus； representation； input； rats； retrieval； pathways； objects； monkey

來源出版物：Cell Reports，2014，9（3）: 893-901聯(lián)系郵箱：Leutgeb，Stefan； sleutgeb@ucsd.edu

The irregular firing properties of thalamic head direction cells mediate turn-specific modulation of the directional tuning curve

Tsanov，Marian； Chah，Ehsan； Noor，Muhammad S； et al.

Abstract： Head direction cells encode an animal's heading in the horizontal plane. However，it is not clear why the directionality of a cell's mean firing rate differs for clockwise，compared with counterclockwise，head turns（this difference is known as the "separation angle"）in anterior thalamus. Here we investigated in freely behaving rats whether intrinsic neuronal firing properties are linked to this phenomenon. We found a positive correlation between the separation angle and the spiking variability of thalamic head direction cells. To test whether this link is driven by hyperpolarization-inducing currents，we investigated the effect of thalamic reticular inhibition during high-voltage spindles on directional spiking. While the selective directional firing of thalamic neurons was preserved，we found no evidence for entrainment of thalamic head direction cells by high-voltage spindle oscillations. We then examined the role of depolarization-inducing currents in the formation of separation angle. Using a single-compartment Hodgkin-Huxley model，we show that modeled neurons fire with higher frequencies during the ascending phase of sinusoidal current injection（mimicking the head direction tuning curve）when simulated with higher high-threshold calcium channel conductance. These findings demonstrate that the turn-specific encoding of directional signal strongly depends on the ability of thalamic neurons to fire irregularly in response to sinusoidal excitatory activation. Another crucial factor for inducing phase lead to sinusoidal current injection was the presence of spike-frequency adaptation current in the modeled neurons. Our data support a model in which intrinsic biophysical properties of thalamic neurons mediate the physiological encoding of directional information.

Keywords： head direction； anterior thalamus； high-voltage spindles； Hodgkin-Huxley model

來源出版物：Journal of Neurophysiology，2014，112（9）: 2316-2331聯(lián)系郵箱：O'Mara，SM； smomara@tcd.ie

Nucleus reuniens of the thalamus contains head direction cells

Jankowski，Maciej M.； Islam，Md Nurul； Wright，Nicholas F； et al.

Abstract： Discrete populations of brain cells signal heading direction，rather like a compass. These 'head direction' cells are largely confined to a closely-connected network of sites. We describe，for the first time，a population of head direction cells in nucleus reuniens of the thalamus in the freely-moving rat. This novel subcortical head direction signal potentially modulates the hippocampal CA fields directly and，thus，informs spatial processing and memory.

Keywords： Rhomboid nuclei； midline thalamus； place fields； rat； hippocampus； populations； projections； memory

來源出版物：Elife，2014，112（9）: 2316-2331聯(lián)系郵箱：O'Mara，SM； smomara@tcd.ie

Spatial representations of place cells in darkness are supported by path integration and border information

Zhang，Sijie； Schoenfeld，F(xiàn)abian； Wiskott，Laurenz； et al.

Abstract： Effective spatial navigation is enabled by reliable reference cues that derive from sensory information from the external environment，as well as from internal sources such as the vestibular system. The integration of information from these sources enables dead reckoning in the form of path integration. Navigation in the dark is associated with the accumulation of errors in terms of perception of allocentric position and this may relate to error accumulation in path integration. We assessed this by recording from place cells in the dark under circumstances where spatial sensory cues were suppressed. Spatial information content，spatial coherence，place field size，and peakand infield firing rates decreased whereas sparsity increased following exploration in the dark compared to the light. Nonetheless it was observed that place field stability in darkness was sustained by border information in a subset of place cells. To examine the impact of encountering the environment's border on navigation，we analyzed the trajectory and spiking data gathered during navigation in the dark. Our data suggest that although error accumulation in path integration drives place field drift in darkness，under circumstances where border contact is possible，this information is integrated to enable retention of spatial representations.

Keywords： sensory； hippocampus； CA1； place cells

來源出版物：Frontiers in Behavioral Neuroscience，2014，8: 222聯(lián)系郵箱：Manahan-Vaughan，D； dmv-igsn@rub.de

Resolving the active versus passive conundrum for head direction cells

Shinder，M. E.； Taube，J. S

Abstract： Head direction（HD）cells have been identified in a number of limbic system structures. These cells encode the animal's perceived directional heading in the horizontal plane and are dependent on an intact vestibular system. Previous studies have reported that the responses of vestibular neurons within the vestibular nuclei are markedly attenuated when an animal makes a volitional head turn compared to passive rotation. This finding presents a conundrum in that if vestibular responses are suppressed during an active head turn how is a vestibular signal propagated forward to drive and update the HD signal？ This review identifies and discusses four possible mechanisms that could resolve this problem. These mechanisms are:（1）the ascending vestibular signal is generated by more than just vestibular-only neurons，（2）not all vestibular-only neurons contributing to the HD pathway have firing rates that are attenuated by active head turns，（3）the ascending pathway may be spared from the affects of the attenuation in that the HD system receives information from other vestibular brainstem sites that do not include vestibular-only cells，and（4）the ascending signal is affected by the inhibited vestibular signal during an active head turn，but the HD circuit compensates and uses the altered signal to accurately update the current HD. Future studies will be needed to decipher which of these possibilities is correct.

Keywords： head direction； navigation； passive movement； self-motion； spatial orientation； vestibular

來源出版物：Neuroscience，2014，270: 123-138聯(lián)系郵箱：Taube，J. S； jeffrey.taube@dartmouth.edu

Medial Entorhinal Grid Cells and Head Direction Cells Rotate with a T-Maze More Often During Less Recently Experienced Rotations

Gupta，Kishan； Beer，Nathan J. ；Keller，Lauren A； et al.

Abstract： Prior studies of head direction（HD）cells indicate strong landmark control over the preferred firing direction of these cells，with few studies exhibiting shifts away from local reference frames over time. We recorded spiking activity of grid and HD cells in the medial entorhinal cortex of rats，testing correlations of local environmental cues with the spatial tuning curves of these cells' firing fields as animals performed continuous spatial alternation on a T-maze that shared the boundaries of an open-field arena. The environment was rotated into configurations the animal had either seen or not seen in the past recording week. Tuning curves of both cell types demonstrated commensurate shifts of tuning with T-maze rotations during less recent rotations，more so than recent rotations. This strongly suggests that animals are shifting their reference frame away from the local environmental cues over time，learning to use a different reference frame more likely reliant on distal or idiothetic cues. In addition，grid fields demonstrated varying levels of "fragmentation" on the T-maze. The propensity for fragmentation does not depend on grid spacing and grid score，nor animal trajectory，indicating the cognitive treatment of environmental subcompartments is likely driven by task demands.

Keywords： entorhinal cortex； experience； fragmentation； grid cells； head direction cells

來源出版物：Cerebral Cortex，2014，24（6）: 1630-1644聯(lián)系郵箱：Gupta，Kishan； kishang@bu.edu

Parvalbumin interneurons provide grid cell-driven recurrent inhibition in the medial entorhinal cortex

Buetfering，Christina； Allen，Kevin； Monyer，Hannah

Abstract： Grid cells in the medial entorhinal cortex（MEC）generate metric spatial representations. Recent attractor-network models suggest an essential role for GABAergic interneurons in the emergence of the grid-cell firing pattern through recurrent inhibition dependent on grid-cell phase. To test this hypothesis，we studied identified parvalbumin-expressing（PV+）interneurons that are the most likely candidate for providing this recurrent inhibition onto grid cells. Using optogenetics and tetrode recordings in mice，we found that PV+ interneurons exhibited high firing rates，low spatial sparsity and no spatial periodicity. PV+ interneurons inhibited all functionally defined cell types in the MEC and were in turn recruited preferentially by grid cells. To our surprise，we found that individual PV+ interneurons received input from grid cells with various phases，which most likely accounts for the broadly tuned spatial firing activity of PV+ interneurons. Our data argue against the notion that PV+ interneurons provide phase-dependent recurrent inhibition and challenge recent attractor-network models of grid cells.

Keywords： olfactory-bulb output； positive interneurons； gamma oscillations； phase precession； path-integration； neurons； rat； hippocampus；model； map

來源出版物：Nature Neuroscience，2014，17（5）: 710聯(lián)系郵箱：Monyer，Hannah； h.monyer@dkfz-heidelberg.de

Spatial coding and attractor dynamics of grid cells in the entorhinal cortex

Burak，Yoram

Abstract： Recent experiments support the theoretical hypothesis that recurrent connectivity plays a central role within the medial entorhinal cortex，by shaping activity of large neural populations，such that their joint activity lies within a continuous attractor. This conjecture involves dynamics within each population（module）of cells that share the same grid spacing. In addition，recent theoretical works raise a hypothesis that，taken together，grid cells from all modules maintain a sophisticated representation of position with uniquely large dynamical range，when compared with other known neural codes in the brain. To maintain such a code，activity in different modules must be coupled，within the entorhinal cortex or through the hippocampus.

Keywords： phase precession； oscillatory interference； 3-dimensional space； population codes； path-integration； firing fields； cognitive map；place cells； rat； representation

來源出版物：Current opinion in Neurobiology，2014，25:169-175聯(lián)系郵箱：Burak，Yoram； yoram.burak@elsc.huji.ac.il

Encoding of Head Direction by Hippocampal Place Cells in Bats

Rubin，Alon； Yartsev，Michael M.； Ulanovsky，Nachum

Abstract： Most theories of navigation rely on the concept of a mental map and compass. Hippocampal place cells are neurons thought to be important for representing the mental map； these neurons become active when the animal traverses a specific location in the environment（the "place field"）. Head-direction cells are found outside the hippocampus，and encode the animal's head orientation，thus implementing a neural compass. The prevailing view is that the activity of head-direction cells is not tuned to a single place，while place cells do not encode head direction. However，little work has been done to investigate in detail the possible head-directional tuning of hippocampal place cells across species. Here we addressed this by recording the activity of single neurons in the hippocampus of two evolutionarily distant bat species，Egyptian fruit bat and big brown bat，which crawled randomly in three different open-field arenas. We found that a large fraction of hippocampal neurons，in both bat species，showed conjunctive sensitivity to the animal's spatial position（place field）and to its head direction. We introduced analytical methods to demonstrate that the head-direction tuning was significant even after controlling for the behavioral coupling between position and head direction. Surprisingly，some hippocampal neurons preserved their head direction tuning even outside the neuron's place field，suggesting that "spontaneous" extra-field spikes are not noise，but in fact carry head-direction information. Overall，these findings suggest that bat hippocampal neurons can convey both map information and compass information.

Keywords： spatial representation system； freely-moving rats； entorhinal cortex； grid cells； echolocating bats； firing properties； unit-activity；position； ca1； map

來源出版物：Journal of Neuroscience，2014，34（3）: 1067-1080聯(lián)系郵箱：Ulanovsky，Nachum； nachum.ulanovsky@weizmann.ac.il

（責任編輯王帥帥，衛(wèi)夏雯）

Representation of spatial orientation by the intrinsic dynamics of the head-direction cell ensemble： A theory

Zhang，K

The head-direction（HD）cells found in the limbic system in freely moving rats represent the instantaneous head direction of the animal in the horizontal plane regardless of the location of the animal. The internal direction represented by these cells uses both self-motion information for inertially based updating and familiar visual landmarks for calibration. Here，a model of the dynamics of the HD cell ensemble is presented. The stability of a localized static activity profile in the network and a dynamic shift mechanism are explained naturally by synaptic weight distribution components with even and odd symmetry，respectively. Under symmetric weights or symmetric reciprocal connections，a stable activity profile close to the known directional tuning curves will emerge. By adding a slight asymmetry to the weights，the activity profile will shift continuously without disturbances to its shape，and the shift speed can be controlled accurately by the strength of the odd-weight component. The generic formulation of the shift mechanism is determined uniquely within the current theoretical framework. The attractor dynamics of the system ensures modality-independence of the internal representation and facilitates the correction for cumulative error by the putative local-view detectors. The model offers a specific one-dimensional example of a computational mechanism in which a truly world-centered representation can be derived from observer-centered sensory inputs by integrating self-motion information.

head-direction cell； spatial orientation； attractor dynamics； dynamic shift mechanism； velocity integration； anterior thalamus；postsubiculum

*摘編自《首都醫(yī)科大學學報》2014年35卷5期671～675頁