2014年诺贝尔生理学或医学奖（构成大脑定位系统的细胞）

大脑中的“定位系统”——2014年诺贝尔生理学或医学奖简介

王可，张婷，王晓民

（首都医科大学基础医学院神经生物学系教育部神经变性病重点实验室北京市脑重大疾病研究院北京市脑重大疾病重点实验室，北京100069）

大鼠多通道在体记录

王一男，唐永强，潘璟玮，等

热点追踪

2014年诺贝尔生理学或医学奖（构成大脑定位系统的细胞）

·编者按·

2014年10月6日，瑞典卡罗琳医学院在斯德哥尔摩宣布，将2014年诺贝尔生理学或医学奖授予拥有美国和英国国籍的科学家约翰奥基夫（John O'Keefe）以及两位挪威科学家梅-布利特·莫泽（May-Britt Moser）和爱德华·莫泽（Edvard I. Moser），以表彰他们在发现构建大脑空间定位系统的重要细胞方面所做出的杰出贡献.他们的研究成果揭示了特化细胞如何协作并执行更高的认知功能，为人类高级认知功能提供了细胞基础，开启了人类对记忆、思考等认知过程理解的新篇章.

位置感知和导航能力是大脑的基本功能.位置感知能力赋予人类认识环境中自身的位置以及其他物体的相对位置，而导航能力则是在前期运动和位置记忆的基础上，对距离及方向认知进行整合，从而实现精确定位和路线查找.以上3位科学家首次发现了构成大脑定位系统的细胞并揭示了其潜在的功能.John O'Keefe发现了定位系统中的第一个组成细胞，即位于大脑海马区的一类锥体神经元，被称为“位置细胞”（Place cell）.该细胞使大脑能够将特定的特征信息与相应空间位置联系起来，形成空间位置记忆.May-Britt Moser和Edvard I. Moser夫妇在大脑的内嗅皮层发现了大脑定位系统的另一关键组成细胞——“网格细胞”（Grid cell）.网格细胞将空间位置进行相应的坐标标记，从而实现动物的精确定位及路径寻找.所以当大脑拥有了网格细胞制定的坐标系统以及位置细胞构建的位置特征信息，就形成了相对完整的脑内“地图”，实现了内置GPS的功能.

空间识别及记忆功能丧失是认知功能障碍性疾病的主要临床表现，如阿尔茨海默病（Alzheimer's disease，AD），患病初期就出现了迷路、无法辨识周边环境等症状.因此，该研究有助于理解神经精神疾病中脑回路异常的机制，对脑重大疾病的诊断和治疗提供新的思路.Morser夫妇及John O'Keefe均指出Place cell与Grid cell，以及之前发现的Boundary cell和Head direction cell具有广泛的功能联系，这些神经细胞间的交互作用，以及内嗅皮质与海马之间的环路研究对探索大脑的空间记忆功能具有重要意义.

本专题得到了杨雄里院士（复旦大学脑科学研究院）、林龙年教授（华东师范大学脑功能基因组学研究所）的大力支持.

·热点数据排行·

截至2015年2月11日，中国知网（CNKI）和Web of Science（WOS）的数据报告显示，有关大脑空间定位系统研究的期刊文献分别为13与807条，本刊将相关数据按照：研究机构发文数、作者发文数、期刊发文数、被引用频次进行排行，结果如下.

研究机构发文数量排名（CNKI）

研究机构发文数量排名（WOS）

作者发文数量排名（CNKI）

作者发文数量排名（CNKI）

期刊发文数量排名（CNKI）

期刊发文数量排名（WOS）

根据中国知网（CNKI）数据报告，有关大脑空间定位系统研究的高被引论文排行结果如下.

国内数据库高被引论文排行

根据Web of Science统计数据，有关大脑空间定位系统研究的高被引论文排行结果如下.

国外数据库高被引论文排行

大脑中的“定位系统”——2014年诺贝尔生理学或医学奖简介*

王可，张婷，王晓民

（首都医科大学基础医学院神经生物学系教育部神经变性病重点实验室北京市脑重大疾病研究院北京市脑重大疾病重点实验室，北京100069）

2014年10月6日，瑞典卡罗林斯卡医学院宣布，将本年度诺贝尔生理学或医学奖授予拥有美国和英国国籍的科学家约翰·奥基夫（John O'Keefe）及两位挪威科学家梅一布里特·莫泽（May-Britt Moser）和爱德华·莫泽（Edvard I. Moser），表彰他们发现了大脑中的“内置GPS（global positioning system）”——定位系统，这不仅使自然界生物可以在空间中进行自我定位，同时也为人类高级认知功能提供了细胞基础.

人们如何知道自己的位置？如何从一个地方到另一个地方？如何在大脑中储存方位信息，以便下一次能够找到相同路径？自然界的生物总是能在好奇心驱使探寻外周世界的同时牢记自己回家的路.无论从动物的本能觅食、迁徙行为，还是到经训练后的老马识途、飞鸽传书等技能，都展示了在进化中自然界赋予大脑神奇的定位功能.那么究竟大脑是如何实现对自身定位呢？以上 3位科学家首次发现了构成大脑定位系统的细胞并揭示了其潜在的功能.John O'Keefe发现了定位系统中的第一个组成细胞，即位于大脑海马区的一类锥体神经元，称“位置细胞”（Place cell）.他的研究中指出动物行走到某个特定位置时，对应一些特定Place cell激活，当行走到其他位置时，又有相应的另一些Place cell激活.这使大脑能够将特定的特征信息与相应空间位置联系起来，形成了空间位置记忆.但是单凭特征信息这一点却不能对空间位置进行精确定位，就像如果我们只知道想去地方的样子而不知道具体的地址，依然去不了想去的地方.而May-Britt Moser和Edvard I. Moser夫妇在大脑的内嗅皮质发现了大脑定位系统的另一关键组成细胞——“网格细胞”（Grid cell）.他们发现正是Grid cell将空间位置进行相应的坐标标记，可以实现动物的精确定位及路径寻找.所以当大脑拥有了Grid cell制定的坐标系统以及Place cell构建的位置特征信息，就形成了相对完整的脑内“地图”，实现了内置GPS的功能.这项研究不仅揭示了生物体空间位置记忆的神经机制，也为人工智能及机器人的开发提供了理论基础.此外对一些与记忆相关的疾病，如阿尔茨海默病患者患病初期出现的迷路、无法辨识周边环境等症状，利用大脑定位系统的机制也会帮助我们进一步了解这些患者空间记忆缺失的原理以及为治疗疾病开发脑内植入芯片提供空间.

1获奖者简介

1.1John O'Keefe

John O'Keefe（图1），1939年11月18日出生于美国纽约，拥有美国和英国双重国籍，现任英国伦敦学院大学（University College London，UCL）认知神经科学研究所和解剖学系的教授.

John O'Keefe本科就读于纽约城市学院，1963年获学士学位.博士就读于加拿大麦吉尔大学，攻读生理心理学博士学位，导师为Ronald Melzaek教授.1967年他作为美国国立精神卫生研究所博士后，在UCL和与Ronald Melzaek同为“疼痛门控学说”共同创立者的Patrick mall一起工作.他们的理论对后来许多诺贝尔奖级别的发现（内啡肤）具有直接指导价值.1987年O'Keefe获得UCL教授职位，从此再未离开过UCL，John O'Keefe不但发现了海马体中的Place cell，并且进一步揭示了这类细胞以e相移的方式进行临时编码.2008年O'Keefe获得美国格鲁伯神经学国际研究奖.2013年，John O'Keefe与May-Britt Moser和Edvard I. Moser分享了路易莎·格罗斯·霍维茨生物学或生物化学奖.

1.2May-Britt Moser及Edvard I. Moser夫妇

Edvard I. Moser（图2），1962年4月27日出生于挪威奥勒松，现任挪威科技大学神经科学和心理学教授，特隆赫姆系统神经科学科维理研究所的主任.May-Britt Moser（图2），1963年1月4日出生于挪威福斯纳瓦格.现任挪威科技大学神经科学教授，特隆赫姆系统神经科学计算中心主任.

Moser夫妇本科及研究生均就读于挪威奥斯陆大学，分别于1990年获得学士学位、1995年获得神经生理学博士学位.1994至1996年Moser夫妇在爱丁堡大学神经科学中心作博士后研究，并与John O'Keefe实验室建立合作关系.之后夫妇二人一起回到挪威科技大学，被任命为心理生物学副教授.1998年Edvard I. Moser晋升为神经科学和心理学正教授，2000年May-Britt Moser晋升为神经科学正教授.2002年Moser夫妇共同建立了记忆生物学中心和Kavli研究所，致力于从神经回路和系统水平上理解大脑功能，集中于空间记忆功能的研究.如前所述，Moser夫妇于2013年与John O'Keefe分享了路易莎·格罗斯·霍维茨生物学或生物化学奖.

2主要科学贡献

位置感知和导航能力是大脑的基本功能.位置感知能力赋予人类认识环境中自身的位置以及其他物体的相对位置，而导航能力则是建立在前期运动和位置记忆之上，对距离及方向认知的整合，进行精确定位和路线查找.正是依靠这些空间位置记忆能力来认识及记录周围的环境，并绘制大脑内的“认知地图”.但是大脑中如何产生“认知地图”？随着Place cell及Grid cell的发现为我们逐步揭开了它的神秘机制.

2.1海马区Place cell的发现

有关位置和导航的问题困扰了科学家很长时间.早在17世纪，欧洲经验主义者就认为人们对世界的认识起源于感官印象，可能是一种先验的直觉.其中“空间概念（Space）”被提出，并认为其是思维中固有成分，人们通过空间感知世界.随着实验心理学以及神经科学的发展，1948年，Edward Tolman在研究迷宫中运动的大鼠时，发现它们可以学会导航，并成功通过迷宫，猜想大脑一定是形成了一幅“认知地图”.而随后研究发现若将大鼠海马损伤可导致其无法通过迷宫，并无法对环境中的改变产生响应.

为了更好的研究海马在“认知地图”中可能的作用，1971年John O'Keefe和Dostrovsky利用在体神经电生理方法记录了自由活动大鼠海马体中神经细胞的放电.他们首次在大鼠海马CA1区发现一类独特细胞.当大鼠运动到区域中某一特定位置可使这类神经细胞放电；而在区域的其他位置，并不会引起这类细胞的放电，而这类细胞被称为“Place cell”，引起“Place cell”放电的特定位置称为Place field.John O'Keefe指出不同的Place field对应于不同的Place cell放电，这样海马中很多不同的Place cell放电就形成了一幅所处环境的内在地图.

随着John O'Keefe团队的深入研究，他们发现Place cell还具有学习记忆的功能.研究指出当外界环境发生微小变化时，Place cell与Place field的对应关系并不会发生明显的改变，但是当环境发生很大变化时，Place cell与Place field的关系可以发生重新排列，或者对应新的Place field，形成新的组合并能保持一定时间，这个过程称作“Remapping”.因此，通过不同环境中对不同Place cell的激活，海马可以构造出很多地图，也就是说大脑对环境的记忆是以不同Place cell组合方式储存在海马中.

John O'Keefe对海马Place cell的发现开启了人们对空间记忆的细胞学机制研究，此后不断有研究发现与空间记忆相关的神经元，包括边界细胞（Boundary cell）、头向细胞（Head direction cell）以及随后即将介绍的网格细胞（Grid cell）.这些与空间记忆相关的细胞，相互联系，共同形成大脑的空间定位系统.

2.2内嗅皮质Grid cell的发现

继Place cell的发现后长达30年的空间记忆神经机制研究中，大多科学家更倾向于研究海马内神经网络的调节，直到Moser夫妇在内嗅皮质发现了Grid cell.其实早在Moser夫妇在O'Keefe实验室做博士后研究的时候就提出，Place cell或是空间记忆的调节是否存在海马区以外的机制.神经解剖学研究发现，内嗅皮质的传出纤维是海马神经传入纤维的主要来源，并且大部分内嗅皮质的传出纤维投射到海马齿状回及CA3区，经过换元后可投射到背侧海马CA1区；此外也有部分内嗅皮质的传出纤维可直接投射到CA1区，而CA1区正是Place cell所在区域.因此Morser夫妇对内嗅皮质神经元放电与空间记忆功能进行了大量研究.

2005年，Moser夫妇首先在内嗅皮质记录到一类与Place cell放电形式相似的细胞，这类细胞放电也表现出对特定位置的反应性.但是与Place cell不同的是，它们的放电不依赖于外界的环境，而是在运动区域内发生重复性规律放电，如果将每个放电区域作为一个节点，并将节点相连就会形成一种类似于蜂巢式的六边形网格，而这种细胞就称Grid cell.研究发现无论运动区域的大小及形状变化，放电形成的网格总是布满整个运动空间范围，并且保持网格大小及结构不变，而只改变网格的数目.此外研究也指出即使在黑暗情况下，大鼠Grid cell放电也可形成稳定的网格.Moser夫妇的研究还指出不同内嗅皮质区域的Grid cell放电形成的网格大小不同，表现为内嗅皮质腹侧的Grid cell放电形成网格大于中间层的Grid cell放电形成的网格.正是由于这些独特且精确的网格放电模式赋予了Grid cell编码空间环境及导航的能力.Grid cell网格放电结构使得内嗅皮质与整个空间环境之间建立了稳定而有效地靶向关系，且能保障在空间矢量关系上发生同步变化.

随着研究的深入，Morser夫妇及John O'Keefe均指出Grid cell与之前发现的Place cell，Boundary cell和Head direction cell具有广泛的功能联系（Head direction cell的放电与动物头部转动的方向及角度有关；而当动物在封闭环境中碰到阻挡则会引起Bound-ary cell的放电）.其中Grid cell可整合Boundary cell，Head direction cell及视觉和本体感觉的距离信息，经过分析不同内嗅皮质区域的Grid cell放电，并通过一些复杂的算法就可确定动物自身在这个六边形网格中的精确坐标.此外，研究发现Grid cell，Boundary cell及Head direction cell均可投射到海马Place cell，这些与空间位置相关的各类细胞相互影响，最终决定Place cell的放电形式.然而Grid cell虽然为空间位置找到了坐标系，但是如果想长期保存这样的信息还需要大脑海马区的记忆储存功能配合，因此对Grid cell与Place cell交互作用的研究以及内嗅皮质与海马体之间的环路对于完善空间记忆的研究也具有重要意义.

3科学意义

（1）该研究有助于人类认识人脑的高级功能，是实现从神经元放电到认知功能联系的典型模式.

尽管科学家在30年前就已经弄清秀丽隐杆线虫（Caenorhabditis elegans）302个神经元之间的连接方式，但迄今为止，就连这种低级生物最基本的生存行为（如进食和交配）是如何产生的，也还不清楚.这中间所失的一环，就是神经元活动和特定行为之间的关系.该研究在细胞层面共同实现大脑对位置和路径的认知，成为这一领域研究的典型代表.

奥巴马政府已于去年宣布启动“脑计划”（Brain Research through Advancing Innovative Neuroteehnologies，BRAIN），在2014年的启动资金为1亿多美元，致力于开发能记录大群神经元，甚至是整片脑区的电活动的新技术.而在美国之外，全球还有很多其他大规模的脑科学项目.比如，欧盟的“人类大脑计划”（The Human Brain Projeet），这一计划为期十年，将耗资16亿美元，致力于构建能真正模拟人脑的超级计算机.尽管中国的脑科学研究与世界先进水平仍有差距，如能推动中国脑科学计划的实施将会从整体上提高中国脑科学的研究水平.

（2）该研究有助于理解神经精神疾病中脑回路异常的机制，对脑重大疾病的诊断和治疗提供新的思路.

近年来随着脑功能成像的发展，以及对神经外科手术患者的研究均发现在人脑中存在Place cell和Grid cell，并且其放电形式及功能与动物研究一致，具有空间识别及记忆功能.

空间识别及记忆功能丧失是认知功能障碍性疾病的主要临床表现.如阿尔茨海默病（Alzheimer's disease，AD）患病初期就出现了迷路、无法辨识周边环境等症状.2008年，John O'Keefe将对Place cell的研究推进到了更有实际意义的工作中，他发现在16个月Tg2576转基因AD小鼠中，出现了明显的Place cell空间识别功能障碍，表现为Place cell放电减少以及Place field增大，同时研究还指出Place cell的功能障碍程度与AD小鼠的认知行为以及海马Ap斑块的沉积密度高度相关，这提示对Place cell功能检测可以敏感的反映AD小鼠认知功能及病理损伤程度，同时也可以成为AD疗效评价的良好指标.

4诸多相关问题有待揭示

大脑“定位系统”的发现和研究已取得成果，随之有很多相关问题有待进一步揭示.Morser夫妇及John O'Keefe均指出Grid cell与之前发现Place cell，Boundary cell和Head direction cell具有广泛的功能联系，对Grid cell与Place cell交互作用以及内嗅皮质与海马之间的环路研究对于完善空间记忆的研究将具有重要意义.Grid cell在内嗅皮质被发现，而病理学研究指出在AD病理过程中最早受累的区域是内嗅皮质，那么内嗅皮质中Grid cell究竟对AD的早期症状的意义如何？另外，路径导航方式在男性和女性之间有较大差别，男性擅长定向策略，而女性擅长路线策略，那么，大脑“定位系统”在男性和女性中是否也存在差异？对于“路痴”，是否也存在细胞水平的差别？这些差异是否可以通过后天学习与训练而发生改变？

总之，John O'Keefe和Moser夫妇的研究工作为认知科学研究领域展现了一幅生动的有“迹”可循的蓝图，该研究成果对空间行为和空间探索的细胞学基础进行揭示，对于破译思想和行为背后的脑活动模式，甚至整个认知科学领域的发展都作出了巨大贡献.

·高被引论文摘要·

被引频次：11

大鼠多通道在体记录

王一男，唐永强，潘璟玮，等

多通道在体记录技术，能在自由活动的动物脑内，观察和记录局部脑区群体神经元的活动状况，是分析大脑神经信息编码的有力工具.要开展多通道在体记录研究，多电极阵列驱动器的设计非常关键，也是实现该技术的一大难点根据转动螺杆推动螺帽移动的机械驱动原理，作者设计了适合大鼠多通道在体记录的、独立可调式16道电极阵列驱动装置.通过该装置，可对16道记录电极中的任意一道进行独立驱动，从而控制每根记录电极在大鼠大脑中的垂直记录位置.运用该多电极阵列驱动装置，对大鼠单侧海马脑区的多通道在体记录表明：在大鼠海马CA1区，存在不同放电波形和放电模式的神经元，它们分别与海马CA1区的锥体神经元和中间神经元相对应.一般锥体神经元动作电位的放电波形较宽放电频率则较低.在海马CA1区还存在编码空间环境中特定位置信息的神经元，被称为位置细胞.这些位置细胞在某一空间环境中有各自对应的反应区域在该区域内，位置细胞的放电频率增加，在区域外则基本维持在一较低的活动水平.

多通道在体记录；大鼠；海马；位置细胞

来源出版物：生物物理学报，2010，26（5）: 397-405

被引频次：3

海马位置细胞研究进展

高洁，隋建峰

摘要：位置细胞是与动物行为活动所处位置密切相关并具有复杂锋电位的海马锥体细胞，是脑内认知地图的基本组成单元.当个体处于特定的“位置野”时，相应的位置细胞呈现最大放电.位置细胞并非单纯的感觉神经元，内、外源性信息输入均可影响位置细胞的放电活动，使位置野表现出一定的可塑性.本文对近年来关于海马位置细胞的发现、分布及其电生理特性等研究进行了综述.

关键词：位置细胞；海马；位置野

来源出版物：生理科学进展，2003，34（2）: 162-164

被引频次：3

网格细胞在空间记忆中的作用

于平，徐晖，尹文娟，等

摘要：网格细胞存在于内嗅皮层，具有显著的空间放电特征，并呈现出网格图样的放电结构.近年来网格细胞的发现及其功能研究，为深入阐释空间记忆的神经机制开辟了新的视角.本文详细介绍了网格细胞的发现、神经解剖学联系及空间放电特征；通过网格细胞与位置细胞的对比分析，阐释网格细胞利用自身运动信息进行空间编码的机制，以及在空间记忆中所发挥的路径整合器功能.

关键词：网格细胞；位置细胞；空间记忆；路径整合

来源出版物：心理科学进展，2009，17（6）: 1228-1233联系邮箱：于萍，yupingyp@gmail.com

被引频次：2

记忆过程中海马CA1区神经元的集群放电特征

于萍，袁水霞，李霞，等

摘要：观察空间工作记忆过程中海马CA1区神经元群的放电特征.应用多通道神经元集群放电记录技术，同步观察和记录清醒大鼠在执行延迟选择任务时的行为轨迹以及海马CA1区神经元的放电活动.发现：海马CA1区位置细胞的位置野是在学习过程中逐渐形成并可消退；部分位置细胞的放电对未来目标定向性行为具有预测作用；在空间工作记忆过程中，神经元放电之间的相关性加强，神经元之间以及神经元与局部场电位之间存在相位编码方式.结果提示海马CA1区神经元参与对空间信息的初级编码和加工，并为未来行为决策提供有效信息，而且海马对信息的加工是通过局部神经网络进行，时间编码可能是海马信息加工的重要方式之一.

关键词：空间工作记忆；海马；位置细胞；位置野；多通道记录

来源出版物：心理学报，2011，43（8）: 917-928联系邮箱：郭春彦，guocy@mail.cnu.edu.cn

被引频次：1

海马位置细胞对空间信息的处理

左艳芳，罗非，崔彩莲

摘要：海马位置细胞接收各种来源的空间信息后，可对这些信息进行加工处理，在海马内形成认知地图或加强联合皮层内细胞集群的突触联系以形成对空间位置的永久记忆.海马内的空间信息输出后，在伏核（nucleus accumbens，NAC）内与其它来源的信息进行整合，最终通过运动环路形成目标指向性行为.

关键词：位置细胞；海马；位置野；位置线索；认知地图

来源出版物：生理科学进展，2006，37（1）: 6-10

被引频次：1

海马位置细胞空间信息处理机制的研究进展

胡波，隋建峰

摘要：位置细胞是具有位置特异性和复杂锋电位的海马锥体细胞.三十多年来，人们致力于研究位置细胞放电与空间信息处理之间的关系，并取得了可喜的进展.但遗憾的是，位置细胞处理空间信息的详细机制至今仍不清楚.本文就近年来关于海马位置细胞空间信息处理机制的研究进展做一综述.

关键词：海马；位置细胞；位置野；放电

来源出版物：中华神经医学杂志，2005，4（4）: 416-418

被引频次：353

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

被引频次：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

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

被引频次：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

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

被引频次：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

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

被引频次：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

来源出版物：Progress in Neurobiology，1998，55（3）: 225-256联系邮箱：Taube，JS； jeffrey.taube@dartmouth.edu

被引频次：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

来源出版物：Cell，1996，87（7）: 1351-1361

被引频次：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

来源出版物：Hippocampus，1999，9（4）: 464-480联系邮箱：Rolls，ET； Edmund.Rolls@psy.ox.ac.uk

被引频次：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来源出版物：Journal of Neurophysiology，1995，74（5）: 1953-1971

被引频次：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

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

被引频次：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

来源出版物：Network-Computation In Neural Systems，2006，17（4）: 447-465联系邮箱：Elliot，Thomas； Edmund.Rolls@psy.ox.ac.uk

·推荐论文摘要·

解码大脑的空间方位认知

马晓宇，林龙年

摘要：在过去的几十年间，与大脑空间方位认知功能相关的位置细胞、网格细胞、头朝向细胞和边界细胞陆续被发现，它们共同构成了大脑内部的导航定位系统.O'Keefe教授和Moser夫妇这三位科学家也正是由于发现了位置细胞和网格细胞，而共同获得了2014年的诺贝尔生理学或医学奖.

关键词：空间方位认知；海马；位置细胞；内嗅皮层；网格细胞

来源出版物：生命科学，2014，26（12）: 1248-1254

多通道在体记录技术——神经元放电与节律性场电位间的相位分析方法

王策群，陈强，张栌，等

摘要：本文旨在介绍神经元放电序列与节律性场电位间的相位分析方法.多通道在体记录技术能同时记录群体神经元和局部场电位的活动信号.神经元的放电活动一般表征为放电时间序列；而在局部场电位信号中，则包含有不同频率成分的周期性节律振荡.相位分析主要考察神经元放电时刻与周期性节律场电位相位间的相互关系.具体分析时，先运用Hilbert变换计算出某一频段节律场电位信号的瞬时相位值，然后再计算某一神经元放电序列中每个动作电位相对于该节律场电位的放电相位，最后通过考察这些放电相位的分布特性，来判断该神经元与该节律场电位相位间的放电相位关系.如一神经元放电序列对某种节律场电位的相位分布经统计检验不是随机的，则表明该神经元对这种节律场电位有放电锁相关系.Theta相位进动则是一种特殊的神经元放电与周期性节律场电位间的相位关系，也是海马位置细胞放电的基本特性之一.海马位置细胞在位置野内一般呈theta节律簇状放电模式，而相位进动是指每一theta波内放电的theta相位，相对上一theta波会逐渐提前.这一现象可通过对位置细胞放电的theta相位和动物实时位置使用线性模型来描述；并运用圆周线性相关分析法，计算它们之间的相关系数，从而研究位置细胞在位置野中的放电相对于theta相位的进动情况.通过相位分析，可以帮助我们了解神经元放电与节律性场电位信号间的时间信息编码特性.

关键词：多通道在体记录；放电锁相；位置细胞；相位进动

来源出版物：生理学报，2014，66（6）:746-755联系邮箱：林龙年，lnlin@brain.ecnu.edu.cn

大鼠海马结构CA1位置细胞对感觉错配适应的相关反应

邹丹，吴敏范，金戈，等

摘要：目的：观察大鼠经过学习其海马结构接受视觉-前庭-本体感觉错配格局并将其视为匹配的状态后CA1位置细胞的电活动，为揭示海马结构可编码感觉输入的任何组合提供依据.方法：应用微电极细胞外记录方法，记录清醒大鼠在适应视觉-前庭-本体感觉错配条件后海马结构CA1位置细胞神经元放电情况.结果：56个位置细胞中，29个神经元在正向状态中有显著的空间放电（正向相关神经元），19个神经元在反向状态中有显著的空间放电（反向相关神经元）.位置野内放电频率的分布呈现不对称及负偏斜.结论：大鼠海马结构位置细胞可编码不能自然发生的新的感觉输入配置，更新海马结构比较器内的信息.

关键词：感觉错配；海马；位置细胞；神经元放电

来源出版物：中国医科大学学报，2014，43（2）: 146-149联系邮箱：邹丹，zoudan1166@hotmail.com

视觉-前庭感觉-本体感觉错配适应大鼠海马CA1区位置细胞的放电特征

邹丹，金戈，符文双

摘要：目的：观察大鼠经过学习其海马结构接受视觉-前庭感觉-本体感觉错配格局并将其视为匹配的状态后 CA1区位置细胞的电活动，为揭示海马结构可编码感觉输入的任何组合提供依据.方法：建立视觉-前庭感觉-本体感觉错配格，根据对海马结构齿状回 θ节律的记录及其电功率的计算，获知大鼠适应该感觉冲突后，应用钨丝微电极细胞外记录方法，记录清醒大鼠在适应视觉-前庭感觉-本体感觉错配条件后海马 CA1区位置细胞神经元集群放电情况.结果：56个位置细胞中，14个（25.0%）神经元在感觉正配及错配条件下均有位置稳定的空间放电（双向移动相关经验非依赖神经元），33个（58.9%）神经元在感觉正配及错配条件下依次出现位置不稳的空间放电（双向移动相关经验依赖神经元）.经验非依赖神经元的位置野长度及非对称指数的均值大于经验依赖型神经元，差异有统计学意义（P＜0.01，P＜0.05）.此外，位置野内放电频率的分布呈现出不对称及负偏斜.结论：动物在适应自然情况下不可能出现的新的感觉配置后，海马结构能编码这一配置并能更新其储存的记忆，接受新的配置作为匹配状态.海马结构可能编码感觉输入的任何组合.

关键词：感觉错配；适应；海马；位置细胞；神经元放电

来源出版物：第二军医大学学报，2014，35（6）: 592-597联系邮箱：邹丹，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

来源出版物：Current Biology，2015，25（1）: 103-108联系邮箱：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.

来源出版物：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.

来源出版物：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

来源出版物：Nature Reviews Neuroscience，2014，15（7）: 466-481联系邮箱：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

来源出版物：Philosophical Transactions of the Royal Society B-Biological Sciences，2014，369（1635）文献号：20120516

联系邮箱：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

来源出版物：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

来源出版物：Neuron，2014，84（6）: 1120-1125联系邮箱：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

来源出版物：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

来源出版物：Cell Reports，2014，9（3）: 893-901联系邮箱：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

来源出版物：Journal of Neurophysiology，2014，112（9）: 2316-2331联系邮箱：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

来源出版物：Elife，2014，112（9）: 2316-2331联系邮箱：O'Mara，SM； smomara@tcd.ie

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

Zhang，Sijie； Schoenfeld，Fabian； 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

来源出版物：Frontiers in Behavioral Neuroscience，2014，8: 222联系邮箱：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

来源出版物：Neuroscience，2014，270: 123-138联系邮箱：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

来源出版物：Cerebral Cortex，2014，24（6）: 1630-1644联系邮箱：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

来源出版物：Nature Neuroscience，2014，17（5）: 710联系邮箱：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

来源出版物：Current opinion in Neurobiology，2014，25:169-175联系邮箱：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

来源出版物：Journal of Neuroscience，2014，34（3）: 1067-1080联系邮箱：Ulanovsky，Nachum； nachum.ulanovsky@weizmann.ac.il

（责任编辑王帅帅，卫夏雯）

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

*摘编自《首都医科大学学报》2014年35卷5期671～675页