2014年诺贝尔生理医学奖获得者科研方法初探

诺贝尔奖获得者的科学研究方法与思路科学研究是人类社会进步的引擎，而诺贝尔奖则是科学界的最高荣誉。

诺贝尔奖获得者们以其杰出的贡献和创新性研究方法在各自的领域取得了成功。

在本文中，我们将探讨一些诺贝尔奖获得者常用的科学研究方法和思路。

一、坚持创新思维诺贝尔奖获得者们的研究方法中最显著的一个特点就是坚持创新思维。

无论是在医学、物理还是化学领域，他们都试图找到以往未被发现或未被充分研究的问题，并提出全新的解决方案。

他们敢于挑战传统观念，冒险尝试新的理论和实验，从而推动了学科的进步。

二、跨领域合作诺贝尔奖获得者们通常倾向于与其他领域的科学家合作，以达到更深层次的研究成果。

他们深刻理解到，只有与不同专业的科学家合作，才能将多个学科的知识融合在一起，从而攻克更为复杂的问题。

通过跨领域合作，他们打破了学科间的壁垒，开创了新的研究方向。

三、注重基础研究诺贝尔奖获得者们在科学研究中注重基础研究的重要性。

他们深刻理解到，只有对基础科学问题进行深入的研究，才能够有更广泛的应用和更具有创造性的发现。

他们从最基础的原理出发，通过不断的实验和观察，逐渐解开了自然界的奥秘。

四、长期坚持诺贝尔奖获得者们通常是长期坚持在某个领域进行研究的。

他们对自己所从事的领域有着深厚的兴趣和执着的热爱，经过多年的努力和探索，才能有所突破。

他们的研究耗时费力，但正是这份坚持使他们能够创造出震撼世界的发现。

五、强调实验验证诺贝尔奖获得者们非常重视实验验证的结果。

他们通过实验数据来支撑自己的理论，通过实验结果来验证自己的科学研究成果。

他们严谨而细致的实验态度，使得他们的研究成果更加可靠和有说服力。

六、认真分析数据诺贝尔奖获得者们对实验数据的分析非常认真。

他们深入研究和理解实验结果的背后含义，通过对数据的分析，推断出新的科学规律和信息。

他们的严谨态度使得他们的研究更加全面和深入。

七、不畏失败诺贝尔奖获得者们在科学研究中也经历了一系列的失败和挫折。

然而，他们并不因此而气馁，反而从失败中吸取经验教训，并不断改进自己的研究方法。

The Nobel Assembly at Karolinska Institutet has today decided to awardThe 2014 Nobel Prize in Physiology or Medicine with one half to John O´Keefeand the other half jointly to May-Britt Moser and Edvard I. Moserfor their discoveries of cells that constitute a positioning system in the brainHow do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? Thi s year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Kee fe concluded that these “place cells” formed a map of the room.More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they ca lled “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.The discoveries of John O´Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries –how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?How do we experience our environment?The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered - how would such a map be represented in the brain? John O´Keefe and the place in spaceJohn O´Keefe was fascinated by the problem of how the brain controls behaviour and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment (Figure 1). He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment. O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.May-Britt and Edvard Moser find the coordinatesMay-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in aroom when they discovered an astonishing pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid (Figure 2). Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain (Figure 3).A place for maps in the human brainRecent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.The discovery of the brain’s positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.Key publications:O'Keefe, J., and Dostrovsky, J. (1971). The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely‐moving rat. Brain Research 34, 171-175.O´Keefe, J. (1976). Place units in the hippocampus of the freely moving rat. Experimental Neurology 51, 78-109.Fyhn, M., Molden, S., Witter, M.P., Moser, E.I., Moser, M.B. (2004) Spatial representation in the entorhinal cortex. Science 305, 1258-1264.Hafting, T., Fyhn, M., Molden, S., Moser, M.B., and Moser, E.I. (2005). Microstructure of spatial map in the entorhinal cortex. Nature 436, 801-806.Sargolini, F., Fyhn, M., Hafting, T., McNaughton, B.L., Witter, M.P., Moser, M.B., and Moser, E.I. (2006). Conjunctive representation of position, direction, and velocity in the entorhinal cortex. Science 312, 758-762.获奖人简介：John O’Keefe was born in 1939 in New York City, USA, and holds both American and British citizenships. He received his doctoral degree in physiological psychology from McGill University, Canada in 1967. After that, he moved to England for postdoctoral training at University College London. He has remained at University College and was appointed Professor of Cognitive Neuroscience in 1987. John O´Keefe is currently Director of the Sainsbury Wellcome Centre in Neural Circuits and Behaviour at University College London.May-Britt Moser was born in Fosnavåg, Norway in 1963 and is a Norwegian citizen. She studied psychology at the University of Oslo together with her future husband and co-Laureate Edvard Moser. She received her Ph.D. in neurophysiology in 1995. She was a postdoctoral fellow at the University of Edinburgh and subsequently a visiting scientist at University College London before moving to the Norwegian University of Science and Technology in Trondheim in 1996. May-Britt Moser was appointed Professor of Neuroscience in 2000 and is currently Director of the Centre for Neural Computation in Trondheim.Edvard I. Moser was born in born 1962 in Ålesund, Norway and has Norwegian citizenship. He obtained his Ph.D. in neurophysiology from the University of Oslo in 1995. He was a postdoctoral fellow together with his wife and co‐Laureate May‐Britt Moser, first at the University of Edinburgh and later a visiting scientist in John O´Keefe´s laboratory in London. In 1996 they moved to the Norwegian University of Science and Technology in Trondheim, where Edvard Moser became Professor in 1998. He is currently Director of the Kavli Institute for Systems Neuroscience in Trondheim.。

人脑中的GPS——解读2014年诺贝尔生理学或医学奖瑞典卡罗林斯卡研究院诺贝尔奖评选委员会10月6日宣布，今年的诺贝尔生理学或医学奖授予英国伦敦大学学院教授约翰·奥基夫（John O’Keefe）、挪威科技大学教授梅·布里特·莫泽（May-Britt Moser）和其丈夫爱德华·莫泽（Edvard I. Moser），因为他们发现了负责大脑定位系统的细胞，由这些细胞组成的系统就是“大脑中的GPS”。

“我们如何知道我们身处何方？我们怎么找到从一个地方到另一个地方的路径？我们如何存储这些信息，从而能够在下一次立即找到这条路？”3位获奖科学家的研究解释了这些问题，人类大脑中一个内置的定位系统可以为人们导航和定位。

奥基夫和位置细胞约翰·奥基夫的贡献在于，他最早发现了动物和人类大脑中的位置细胞，这种位置细胞是构成大脑定位系统的关键细胞之一。

起初，奥基夫被大脑如何控制行为的机理深深吸引。

1960年末，他决定采用神经生理的方法对这一问题进行研究。

奥基夫在博士和博士后的研究中掌握了一些必须技术，如熟练记录动物单个神经元电活动，因此他可以对在盒子或房间内自由跑动的小鼠大脑进行观察。

1971年，奥基夫在记录小鼠大脑内海马体单个神经细胞信号的过程中注意到，当小鼠位于房间内某一特定位置时，一部分神经细胞会被激活。

但当小鼠在房间内的其他位置时，另外一些细胞显示呈激活状态。

例如，小鼠在到达一扇门和一堵墙时，有不同的神经细胞激活。

奥基夫分析认为，这些被激活的细胞就是小鼠感知自身位置的位置细胞，这些位置细胞并非只是简单地接收视觉信息，而是在构建小鼠辨识自己所在房间的“大脑地图”。

同时，海马体会根据不同的环境产生大量的地图，动物处于不同环境时这些地图由大量神经细胞共同作用而形成。

因此，生物体对环境的记忆可以用海马体中神经细胞特定激活组合的方式来进行存储。

此外，基于对小鼠的实验发现，奥基夫和美国亚利桑那大学的神经科学家纳达尔（Lynn Nadel）共同撰写了一本专著《海马是一个认知地图》，详细描述了大脑中的海马是如何帮助动物和人定位的，其本质就是——海马是大脑中一种内在的定位系统。

2014年诺贝尔奖获得者中英文介绍2014年诺贝尔奖获得者名单诺贝尔生理学或医学奖：颁奖日期：10月6日获奖者３：【美&英】科学家约翰·奥基夫、【挪威】科学家梅-布里特·莫泽和爱德华·莫泽夫妇俩获奖理由：发现了大脑中的“内置GPS”——定位和导航系统，从而解答了“我们如何得知我们在哪里”“我们怎样找到路径从一个地点到达另一个地点”以及“我们如何储存这些信息，从而下次需要寻找相同路径时可以立刻获得它们”这几个问题。

这是大脑科学领域重大的基础性突破。

颁奖词节选：“为了解记忆、思维和计划等大脑认知功能拓展了新的空间”诺贝尔物理学奖：颁奖日期：10月7日获奖者３：【日】科学家赤崎勇、【日】天野浩和、【美籍日裔】中村修二获奖理由：表彰他们发明蓝色发光二极管（LED），并因此带来新型的节能光源。

颁奖词节选：“白炽灯照亮20世纪，而ＬＥＤ灯将照亮21世纪”诺贝尔化学奖：颁奖日期：10月8日获奖者３：物理学家：【美】艾力克·贝齐格、【美】W·E·莫纳、【德】斯特凡·W·赫尔获奖理由：表彰他们对于发展超分辨率荧光显微镜做出的卓越贡献。

他们的突破性工作使光学显微技术进入了纳米尺度，从而使科学家们能够观察到活细胞中不同分子在纳米尺度上的运动。

颁奖词节选：“为复杂化学系统创立了多尺度模型”诺贝尔文学奖：颁奖日期：10月9日获奖者１：【法】作家帕特里克·莫迪亚诺代表作：《暗店街》、《八月的星期天》、《青春咖啡馆》、《拉孔布·吕西安》等。

颁奖词节选：“用回忆的艺术唤起了最难以触摸的人类之命运，揭示了作家这项职业的生命世界”诺贝尔和平奖：颁奖日期：10月10日获奖者２：【印度】遗传学家斯瓦米纳坦、【巴基斯坦】人权活动家马拉拉·优素福颁奖词节选：“反抗针对儿童和年轻人的压迫，捍卫了儿童受教育的权利”诺贝尔经济学奖：颁奖日期：10月13日获奖者１：【法】经济学大师让·梯若尔获奖理由：表彰他对市场力量与调控领域研究的贡献颁奖词节选：“阐明了如何理解和监管由数家公司巨头主导的行业”2014 Nobel Prize in PhysicsThe Nobel Prize in Physics 2014 was awarded jointly to Isamu Akasaki, Hiroshi Amano and Shuji Nakamura"for the invention of efficient blue light-emitting diodes which has enabled bright and energy-saving white light sources".2014 Nobel Prize in ChemistryThe Nobel Prize in Chemistry 2014 was awarded jointly to Eric Betzig,Stefan W. Hell and William E. Moerner"for the development of super-resolved fluorescence microscopy".2014 Nobel Prize in Physiology or MedicineThe Nobel Prize in Physiology or Medicine 2014 was awarded with one half to John O'Keefe and 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".2014 Nobel Prize in LiteratureThe Nobel Prize in Literature 2014 was awarded to Patrick Modiano"for the art of memory with which he has evoked themost ungraspable human destinies and uncovered the life-world of the occupation".2014 Nobel Peace PrizeThe Nobel Peace Prize 2014 was awarded jointly to Kailash Satyarthi and Malala Yousafzai "for their struggle against the suppression of children and young people and for the right of all children to education2014 Prize in Economic SciencesThe Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel 2014 was awarded to Jean Tirole "for his analysis of market power and regulation".。

2014年诺贝尔生理学或医学奖解析来自诺贝尔奖官网的消息，2014年诺贝尔生理学或医学奖得主为：美国科学家约翰·奥基弗（John O’Keefe ）、挪威科学家梅-布里特·莫泽（May-Britt Moser）和挪威科学家爱德华·莫泽（Edvard I. Moser）。

他们因为“发现构成大脑定位系统的细胞”而获奖。

获奖理由1971年，约翰·奥基弗发现，当把一只大鼠放到环境中某个特殊的位置时，其大脑中的特定神经细胞会被激活。

当换到其他位置，会导致其大脑中其他的特定神经细胞被激活。

约翰·奥基弗提出，这些“位置细胞”构建了一个外部环境的内部地图。

这些“位置细胞”位于大脑中海马的位置。

2005年，梅-布里特·莫泽和爱德华·莫泽发现，当大鼠通过某些特定位置时，位于海马附近内嗅皮质的另一些的神经细胞被激活。

这些脑区构成一个六边形网格，每个网格细胞在特定的空间图式中起作用。

这些网格细胞共同构成一个坐标系，便于大鼠在三维空间的活动。

网格细胞与位于嗅皮层用于识别动物头部的方向和房间的边界的细胞，以及位于海马的位置细胞一起，共同形成一个网络系统。

这一回路构成了复杂的空间定位系统，这是一个脑内的GPS系统。

人脑中的这一系统似乎有与大鼠脑中的相似的结构。

获奖解析位置感和导航能力是我们存在的基础。

位置感给出了环境位置感知。

导航是指基于先前位置的认知和运动产生的距离感的互相关联。

哲学家和科学家们就有关位置和导航问题曾经有过长期探讨。

200多年前，德国哲学家康德认为，一些心理能力作为先验性知识独立于经验而存在。

他认为空间概念是心灵内在的一种本能，人们必须通过这种本能才能感知这个世界的存在。

到了20世纪中期，随着行为主义心理学的兴起，这些问题开始通过实验手段来解决。

爱德华·托尔曼通过研究大鼠在迷宫中的运动发现，它们可以学习如何导航，他认为大鼠能通过在大脑形成的“认知地图”而找到出路。

2005年至2014年间获得诺贝尔生理与医学奖中与细胞有关的部分姓名：赵丹阳学号2012013053一、2005年，两位合作多年的澳大利亚科学家巴里·马歇尔与罗宾·沃伦，在发现了幽门螺杆菌及其导致胃炎、胃溃疡与十二指肠溃疡等疾病的机理20多年后，终于收到了一份迟来的“贺礼”，分享了2005年诺贝尔生理学或医学奖。

在马歇尔和沃伦发现这种细菌之前，医学界认为正常胃里细菌是不能存活的。

1979年根据活组织切片检查结果，沃伦发现50%左右的病人的胃腔下半部分附生着许多微小的、弯曲状的细菌。

沃伦的发现引来了同行的质疑，但也引起了马歇尔的极大兴趣，他们决定联合对取自100个病人的活组织切片进行研究。

经过反复试验，马歇尔成功地培育出一种当时尚不为人知晓的细菌-后来被命名为幽门螺杆菌。

基于试验结果，马歇尔和沃伦认为，幽门螺杆菌是导致胃炎、十二指肠溃疡或胃溃疡的关键因素。

发现这种细菌，使胃炎、十二指肠溃疡或胃溃疡的诊断治疗变得及其简单。

目前科学家正在研究幽门螺杆菌与胃癌和一些淋巴肿瘤发病之间的联系。

瑞典罗林斯卡研究院诺贝尔奖委员会的一位成员诺马克评论说，澳大利亚人的细菌致溃疡理论是“完全相左于传统的知识和教条”，因为大多数医生都坚信溃疡源自压力和胃酸。

弗吉尼亚大学医学教授的美国胃肠病学协会主席普拉博士指出，两位获奖者的研究“革新了我们对溃疡性疾病的理解”并且“给千百万人带来了希望”。

二、2007年，两名美国人马里奥·卡佩基、奥利弗·史密斯和一名英国人马丁·埃文斯，获得2007年诺贝尔生理学或医学奖。

诺贝尔奖评审委员会发布的公报说，三位科学家“在涉及胚胎干细胞和哺乳动物DNA重组方面有着一系列突破性发现”，为“基因靶向”技术的发展奠定了基础。

卡佩基和史密斯分别独立地发现了利用两段DNA片段的同源重组可以对哺乳动物基因组进行可控的基因修饰。

1981年埃文斯从小鼠胚胎中成功地分离出未分化的胚胎干细胞，这些细胞是生物体所有细胞的来源。

2014诺贝尔奖·生理学或医学奖揭晓 "师徒三人"摘奖项发布时间：2014-10-07 来源：新华网【字号：小中大】瑞典卡罗琳医学院6日在斯德哥尔摩宣布,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·奥基夫以及两位挪威科学家梅-布里特·莫泽和爱德华·莫泽,以表彰他们发现大脑定位系统细胞的研究。

诺贝尔生理学或医学奖揭晓拉开了今年“诺贝尔周”的序幕。

未来一周内,物理学奖、化学奖等奖项将陆续揭晓。

约翰·奥基夫1939年出生于美国纽约市，拥有美国和英国国籍。

在1967年，他在加拿大麦吉尔大学获得了生理心理学博士学位。

在这之后，他到英国伦敦大学学院读博士后。

1987年，他留校担任认知神经科学教授。

目前，约翰·奥基夫教授是伦敦大学学院神经回路与行为中心主任。

梅·布里特·莫泽1963年出生于挪威福斯纳沃格，挪威国籍。

她在奥斯陆大学与她后来的丈夫爱德华·莫泽一起学习心理学。

1995年获得神经生理学博士学位。

她是爱丁堡大学的博士后研究员，随后在英国伦敦大学学院做访问学者，然后在1996年到位于特隆赫姆的挪威大学科学与技术学院工作。

2000年，梅·布里特·莫泽被任命为神经科学教授，目前是特隆赫姆神经计算中心的主任。

爱德华·莫泽1962年出生于挪威奥勒松，挪威国籍。

1995年，他在奥斯陆大学获得神经生理学博士学位。

他与妻子梅·布里特·莫泽一起读博士后，起初是在爱丁堡大学，后来在伦敦约翰·奥基夫的实验室中做一名访问学者。

1996年，他们回到挪威大学科学与技术学院，1998年他升为教授。

他目前是特隆赫姆系统神经科学科维理研究所的主任。

得奖理由诺贝尔奖评选委员会在声明中说:“我们如何知道自己在哪里?我们如何从一个地方到另一个地方?我们如何在大脑中储存信息,以便下一次能够找到相同的路径?”他们发现了大脑的定位系统,即“内部的GPS”,从而使人类能够在空间中定位自我。

浅谈2014年诺贝尔生理学或医学奖获得者的科学研究方法及启示摘要】 2014年诺贝尔生理学或医学奖的公布，标志着科学家对人类大脑机能及疾病治疗的研究迈出了重要一步。

三位诺贝尔奖获得者的研究过程中，有许多值得我们学习和借鉴的科学研究方法。

作为中医院校的学生，掌握科学的研究方法，对日后的学习研究大有裨益。

【关键词】 2014年诺贝尔生理学或医学奖科学研究方法启示【中图分类号】R3 【文献标识码】A 【文章编号】2095-1752（2014）28-0292-02一、前言北京时间2014年10月6日，诺贝尔生理学或医学奖公布，英国伦敦大学学院教授John O'Keefe(约翰-奥基夫)、挪威科技大学教授May Britt Moser（梅-布莱特-莫索尔）及丈夫Edvand Moser（爱德华-莫索尔），因发现组成大脑定位系统的细胞群而获得今年诺贝尔生医学奖。

我们在哪里，又要到哪里去？这个看似哲学化的问题，可能很多人都在不经意间想过，往往都停留在了最浅层。

然而又有多少人将其与大脑内的定位系统联系在一起，去发掘人体内在的奥秘？我们每个人都有发现新事物的潜质，然而只有那些善于观察并坚持探索的人，才能感悟到科学的真谛，觅得科学的硕果。

1948年，爱德华·托尔曼提出了“认知地图”的概念，即空间认知过程不是单纯的刺激—反应，而是大脑某些地方可以通过编写地图告诉个体自身位置。

可惜的是，这一假说一直没有得到证实。

1971年，John O Keefe（约翰·奥基夫）在大脑的“海马体”区域发现一种特殊的神经细胞，当实验小鼠在房间内的某一特定位置时其中一部分这样的细胞总是显示激活状态。

而当小鼠在房间内的其他位置时，另外一些细胞则显示激活状态。

奥基夫认为这些是“位置细胞”，它们构成了小鼠对所在房间的地图。

在此基础上，莫泽夫妇于2005年在海马脑区上游的“内嗅皮层”区域发现了“网格细胞”，当小鼠运动不同距离时，特定的神经元会被激活，当内嗅皮层上百万神经元放电情况累计后，小鼠就可以对自己的运动轨迹进行判断。

2014年诺贝尔生理学或医学奖：大脑GPS2014年诺贝尔生理学或医学奖：大脑GPS2014 年诺贝尔生理学或医学奖得主、挪威科学家莫瑟尔夫妇1988年，挪威特隆赫姆，两位心理学专业的学生坐在著名神经科学家皮尔?奥斯卡?安德森（Per Oskar Andersen）的办公室里，向安德森解释为什么必须跟着他学习。

当时安德森正在开展对大脑海马体区域神经细胞活动的研究，海马区是大脑中一个与记忆有关的重要区域。

安德森对此非常犹豫，这名叫作梅-布里特?莫瑟尔（May-Britt Moser）的女生说她和她的丈夫爱德华?莫瑟尔（Edvard Moser）对行为和生理的交集感兴趣。

2013年，接受《纽约时报》采访时，梅-布里特说：“我们在那里坐了好几个小时，他实在没办法让我们走出办公室。

”“我们都来自非学术性家庭和非学术性的地方。

”爱德华说，“我们长大的地方，没人接受任何大学教育，没有任何关于如何做这些事情的秘诀。

”“还有不知道如何礼貌行事。

”梅-布里特插话。

但他们狂热的好奇心和坚定的决心使得安德森最终向他们妥协，收他们做学生。

2005年，莫瑟尔夫妇在大鼠脑部发现了一种导航系统，他们称之为网格细胞（Grid Cell），并因此一举成名，获得今年的诺贝尔生理学和医学奖。

同时获奖的还有他们在英国留学时候的导师、伦敦大学学院的约翰?奥基夫（John O’Keefe），他曾在上世纪70年代发现大脑中用来定位的位置细胞。

2014 年诺贝尔生理学或医学奖得主、美英双国籍科学家约翰?奥基夫当时奥基夫发现，小鼠在房间的某个特定位置时，其大脑海马区的一些神经细胞总是处于激活状态，而小鼠移动到其他位置时，其他神经细胞则被激活。

他因此得出结论：正是这些位置细胞，在大脑中形成了关于房间各点具体特征的“地图”。

然而仅仅拥有地图还不足以为我们导航，因为地图描述了每一个地方的特征，却没有告诉我们这些地点的相对位置。

还需要一个“经纬网”，让地图上每一个地点都有一个独一无二的坐标。

Scientific BackgroundThe B rain’s Navigational Place and Grid Cell SystemThe 2014 Nobel Prize in Physiology or Medicine is awarded to Dr. John M. O’Keefe, Dr. May-Britt Moser and Dr. Edvard I. Moser for their discoveries of nerve cells in the brain that enable a sense of place and navigation. These discoveries are ground breaking and provide insights into how mental functions are represented in the brain and how the brain can compute complex cognitive functions and behaviour. An internal map of the environment and a sense of place are needed for recognizing and remembering our environment and for navigation. This navigational ability, which requires integration of multi-modal sensory information, movement execution and memory capacities, is one of the most complex of brain functions. The work of the 2014 Laureates has radically altered our understanding of these functions.John O’Keefe discovered place cells in the hippocampus that signal position and provide the brain with spatial memory capacity. May-Britt Moser and Edvard I. Moser discovered in the medial entorhinal cortex, a region of the brain next to hippocampus, grid cells that provide the brain with an internal coordinate system essential for navigation. Together, the hippocampal place cells and the entorhinal grid cells form interconnected nerve cell networks that are critical for the computation of spatial maps and navigational tasks. The work by John O’Keefe, May-Britt Moser and Edvard Moser has dramatically changed our understanding of how fundamental cognitive functions are performed by neural circuits in the brain and shed new light onto how spatial memory might be created. IntroductionThe sense of place and the ability to navigate are some of the most fundamental brain functions. The sense of place gives a perception of the position of the body in the environment and in relation to surrounding objects. During navigation, it is interlinked with a sense of distance and direction that is based on the integration of motion and knowledge of previous positions. We depend on these spatial functions for recognizing and remembering the environment to find our way.Questions about these fundamental brain functions have engaged philosophers and scientists for a long time.During the 18th century the German philosopher Immanuel Kant (1724-1804) argued that some mental abilities exist independent of experience. He considered perception of place as one of these innate abilities through which the external world had to be organized and perceived.A concept of a map-like representation of place in the brain was advocated for by the American experimental psychologist Edward Tolman, who studied how animals learn to navigate (Tolman, 1948). He proposed that animals could experience relationships between places and events and that the exploration of the environment gradually resulted in the formation of a cognitive map that enabled animals to navigate and find the optimal path through the environment. In this view, cognitive maps represent the environment as a gestalt that allows the subject to experience the room and navigate.Tolman’s theory opposed the prevailing view among behaviourists that complex behaviours are achieved by chains of sensory-motor response relationships. But it did not address where in the brain these functions may be localized and how the brain computes such complex behaviours. The advent of techniques to record from cells in the brain of animals that were freely moving in the environment, using chronically implanted micro wires (Sturmwasser, 1958), made it possible to approach these questions.Finding the place cellsJohn O’Keefe had a background in physiological psychology, working with Ronald Melzack at McGill University before he moved to the laboratory of the pain researcher Patrick Wall at University College in London, where he started his work on behaving animals in the late 1960s. There he discovered the place cells, when recording from neurons in the dorsal partition of hippocampus, called CA1, together with Dostrovsky, in rats moving freely in a bounded area (O'Keefe and Dostrovsky, 1971) (Figure 1).Figure 1. Place cells. To the right is a schematic of the rat. The hippocampus, where the place cells are located is highlighted. The grey square depicts the open field the rat is moving over. Place cells fire when the animal reaches a particular location in the en vironment. The dots indicate the rat’s location in the arena when the place cell is active. Different place cells in the hippocampus fire at different places in the arena. The firing pattern of these cells was completely unexpected. Place cells were active in a way that had not been seen for any cells in the brain before. Individual place cells were only active when the animal was in a particular place in the environment, namely their place field. By systematically changing the environment and testing different theoretical possibilities for the creation of the place fields O’Keefe showed that place cell firing did not merely reflect activity in sensory neurons, but that it represented a complex gestalt of the environment.Different place cells could be active in different places and the combination of activity in many place cells created an internal neural map representing a particular environment (O'Keefe, 1976; O'Keefe and Conway, 1978). O’Keefe concluded together with Nadel that place cells provide the brain with a spatial reference map system, or a sense of place (O'Keefe and Nadel, 1978). He showed that the hippocampus can contain multiple maps represented by combinations of activity in different place cells that were active at different times in different environments. A specific serial combination of active place cells may therefore represent a unique environment, while other combinations represent other environments. T hrough O’Keefe’s discoveries, the cognitive map theory had found its representation in the brain.A prerequisite for O’Keefe’s experiments was the development of appropriate recording techniques to be used in freely moving animals. Although O’Keefe was an early user of these techniques, he was not the first to record from hippocampal or other nerve cells in intact animals (see O’Keefe and Nadel 1978). However, researchers mostly used restricted behavioural task or strict stimulus-response protocols. In contrast, O’Keefe recorded thecellular activity during natural behaviour, which allowed him to observe the unique place fields and relate the neural activity in the place cells to represent the sense of place.In subsequent experiments, O’Keefe showed that the place cells might have memory functions (O'Keefe and Conway, 1978; O'Keefe and Speakman, 1987). The simultaneous rearrangement in many place cells in different environments was called remapping and O’Keefe showed that remapping is learned, and once it is established, it can be stable over time (Lever et al., 2002). The place cells may therefore provide a cellular substrate for memory processes, where a memory of an environment can be stored as specific combinations of place cells.At first, the proposition that the hippocampus was involved in spatial navigation was met with some scepticism. However, it was later appreciated that the discovery of place cells, the meticulous demonstration that these cells represent a mental map far from primary sensory input, and the proposal that hippocampus contains an inner map that can store information about the environment, were seminal. O’Keefe’s discovery sparked a large number of experimental and theoretical studies on how place cells are engaged in generating spatial information and in spatial memory processes. The general notion from these studies is that the key function of the place cells are to create a map of the environment, although they may also be involved in measuring distance under some circumstances (Ravassard et al., 2013). From hippocampus to grid cells in the entorhinal cortexThrough the 1980s and 1990s the prevailing theory was that the formation of place fields originated within the hippocampus itself. May-Britt Moser and Edvard Moser, who were studying the hippocampus, both during their PhD work in Per Andersen’s laboratory in Oslo and afterwards both as visiting scientists in Richard Morris’ laboratory in Edinburgh and John O’Keefe’s laboratory in London, asked whether the place cell firing can be generated from activity outside hippocampus. The major input to the hippocampus comes from a structure on the dorsal edge of the rat’s brain, the entorhinal cortex. A large part of the output from the entorhinal cortex projects to the dentate gurus in hippocampus, which in turn connect to the region in the hippocampus called CA3, and further to CA1 in the dorsal hippocampus. Interestingly, this is the same the part of the brain in which John O’Keefe first found the place cells. In 2002, the Mosers found that disconnecting projections from the entorhinal cortex through CA3 did not abolish the CA1 place fields (Brun et al., 2002). These findings, and the knowledge that medial entorhinal cortex is also directly and reciprocally connected to the CA1 region, prompted May-Britt Moser and Edvard Moser to look in the medial entorhinal cortex for place coding cells. In a first study they established, similar to what others had shown, that the medial entorhinal cortex contained cells that shared characteristics with the place cells in hippocampus (Fyhn et al., 2004). However, in a later study using larger encounters for the animals to move in, they discovered a novel cell type, the grid cells, that had unusual properties, (Hafting et al., 2005). The grid cells showed an astonishing firing pattern. They were active in multiple places in the open box that together formed nodes of an extended hexagonal grid (Figure 2), similar to the hexagonal arrangements of holes in a beehive.Grid cells in the same area of the medial enthorinal cortex fire with the same spacingand orientation of the grid, but different phasing, so that together they cover every point in the environment.Figure 2. Grid cells.The grid cells are located in the entorhinal cortex depicted in blue. A single grid cell fires when the animal reaches particular locations in the arena. These locations are arranged in a hexagonal pattern.The Mosers found that the distance of the grid fields varies in the medial entorhinal cortex with the largest fields in the ventral part of the cortex. They also showed that the grid formation did not arise out of a simple transformation of sensory or motor signals, but out of complex network activity.The grid pattern had not been seen in any brain cells before! The Mosers concluded that the grid cells were part of a navigation or path integration system. The grid system provided a solution to measuring movement distances and added a metric to the spatial maps in hippocampus.The Mosers further showed that grid cells were embedded in a network in the medial entorhinal cortex of head direction cells and border cells, and in many cases, cells with a combined function (Solstad et al., 2008). Head-direction cells were first described by James Ranck (1985) in another part of the brain, the subiculum. They act like a compass and are active when the head of an animal points in a certain direction. Border cells are active in reference to walls that the animal encounters when moving in a closed environment (Solstad et al., 2008; Savelli, et al. 2008). The existence of border cells was predicted by theoretical modelling by O’Keefe and colleagues (Hartley, et al. 2000). The Mosers showed that the grid cells, the head direction cells, and the border cells, projected to hippocampal place cells (Zhang et al. 2013). Using recordings from multiple grid cells in different parts of the entorhinal cortex, the Mosers also showed that the grid cells are organized in functional modules with different grid spacing ranging in distance from a few centimetres to meters, thereby covering small to large environments.The Mosers further explored the relationship between grid cells and place cells in theoretical models (Solstad et al., 2006), lesion experiments (Bonnevie et al., 2013; Hafting et al., 2008), and in remapping experiments (Fyhn et al. 2007). These and other studies by Mosers and O’Keefe, as well as by others, have shown that there is a reciprocal influence between grid cells in the medial entorhinal cortex and place cells in the hippocampus and that other spatially-tuned cells in the entorhinal cortex, in particular the border cells (Figure 3), may contribute in the generation of the firing pattern of the place cells (Brandon et al., 2011; Koenig et al., 2011; Bush, Berry and Burgess, 2014, Bjerkness et al. 2014).Figure 3. A schematic showing grid cells (blue) and place cells (yellow) in the entorhinal cortex and hippocampus, respectively.The Mosers’ discovery of the grid cells, a spatial metric coordination system, and their identification of the medial entorhinal cortex as a computational centre for spatial representation, is a break-through that opens up new avenues to advance the understanding of the neural mechanisms underlying spatial cognitive functions.The grid and place cell systems are found in many mammalian species including humansSince the initial description of place and grid cells in rat and mice, these cell types have also been found in other mammals (Killian et al., 2012; Ulanovsky et al., 2007; Yartsev et al., 2011, 2013;).Humans have large hippocampal-entorhinal brain structures and these structures have long been implicated in spatial learning and episodic memory (Squire, 2004). A number of studies support the idea that the human brain has a spatial-coding system that is similar to that found in non-human mammals. Thus, researchers have found place-like cells in the hippocampus (Ekstrom et al., 2003; Jacobs et al., 2010) and grid-like cells in the entorhinal cortex (Jacobs et al., 2013) when directly recording from nerve cells in the human brain of patients with epilepsy undergoing pre-surgical investigation. Using functional imaging (fMRI). Doeller et al. (2010) have also provided support for the existence of grid cells in the human entorhinal cortex.The similarity of the hippocampal-entorhinal structure in all mammals and the presence of hippocampal-like structures in non-mammalian vertebrates with navigational capacity suggest that the grid-place cells system is a functional and robust system that may be conserved in vertebrate evolution. The importance of the discovery of place cells and grid cells for research in cognitive neuroscienceIt is an emergent theme that place-coding cells in the hippocampal structures are involved in storing and/or retrieving spatial memories. In the 1950s Scoville and Milner (1957) published their report on the patient Henry Molaison (HM), who had his two hippocampi surgically removed for treatment of epilepsy. The loss of hippocampi caused severe memory deficits, as evident by the clinical observation that HM was unable to encode new memories, while he could still retrieve old memories. HM had lost what has later been named episodic memory (Tulving and Markowitch 1998), referring to our ability to remember self-experienced events. There is no direct evidence that place cells are coding episodic memory. However, place cells can encode not only for the current spatial location, but also where the animal has just been and where it is going next (Ferbinteanu and Shapiro, 2003). The past and present may also be overlapping in time in place cells when animals are rapidly tele-transported between two physical different environments (Jezek et al., 2011). An encoding of places in the past and present might allow the brain to remember temporally ordered representations of events, like in the episodic memory.After a memory has been encoded, the memory undergoes further consolidation, e.g. during sleep. Ensemble recording with multi-electrodes in sleeping animals has made possible the study of how memories of spatial routes achieved during active navigation are consolidated. Groups of place cells that are activated in a particular sequence during the behaviour display the same sequence of activation in episodes during the subsequent sleep (Wilson and McNaughton, 1994). This replay of place cell activity during sleep may be a memoryconsolidation mechanism, where the memory is eventually stored in cortical structures.Together the activity of place cells may be used both to define the position in the environment at any given time, and also to remember past experiences of the environment. Maybe related to this notion is the findings that the hippocampus of London taxi drivers, which undergoes extensive training to learn how to navigate between thousands of places in the city without a map, grew during the year long training period and that the taxi drivers after this training had significantly larger hippocampal volume than control subjects (Magurie et al. 2000, Woollett and Maguire, 2011). Relevance for humans and medicine Brain disorders are the most common cause of disability and despite the major impact on people’s life and on the society, there is no effective way to prevent or cure most of these disorders. The episodic memory is affected in several brain disorders, including dementia and Alzheimer’s disease. A better understanding of neural mechanisms underlying spatial memory is therefore important, and the discoveries of place and grid cells have been a major leap forward to advance this endeavour. O’Keefe and co-workers have showed in a mouse model of Alzheimer’s disease that the degradation of place fields correlated with the deterioration of the animals’ spatial memory (Cacucci et al., 2008). There is no immediate translation of such results to clinical research or practice. However, the hippocampal formation is one of the first structures to be affected in Alzheimer’s disease and knowledge about the brain’s navigational system might help understand the cognitive decline seen in patients with this diseases. ConclusionsThe discoveries of place and grid cells by John O’Keefe, May-Britt Moser and Edvard I. Moser present a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. The discoveries have profoundly promoted new research with grid and place cell systems now found in many mammals, including humans. Studies of the navigation system have opened new avenues for studying how cognitive processes are computed in the brain.Ole Kiehn and Hans ForssbergKarolinska InstitutetOle Kiehn, MD, PhDProfessor of Neuroscience, Karolinska Institutet Member of the Nobel CommitteeMember of the Nobel AssemblyHans Forssberg, MD, PhDProfessor of Neuroscience , Karolinska Institutet Adjunct Member of the Nobel Committee Member of the Nobel Assembly Illustrations: Mattias KarlenCited literatureBjerknes, T.L., Moser, E.I. and Moser, M.B. (2014). Representation of geometric borders in the developing rat. Neuron, 82(1), 71-78.Bonnevie, T., Dunn, B., Fyhn, M., Hafting, T., Derdikman, D., Kubie, J.L., Roudi, Y., Moser, E.I., and Moser, M.B. 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诺贝尔生理学或医学奖历年获奖者(1901-2014)时间得主国家得奖原因1901年埃米尔·阿道夫·冯·贝林德国“对血清疗法的研究，特别是在治疗白喉应用上的贡献，由此开辟了医学领域研究的新途径，也因此使得医生手中有了对抗疾病和死亡的有力武器”1902年罗纳德·罗斯英国“在疟疾研究上的工作，由此显示了疟疾如何进入生物体，也因此为成功地研究这一疾病以及对抗这一疾病的方法奠定了基础”1903年尼尔斯·吕贝里·芬森丹麦“在用集中的光辐射治疗疾病，特别是寻常狼疮方面的贡献，由此开辟了医学研究的新途径”1904年伊万·巴甫洛夫俄罗斯“在消化的生理学研究上的工作，这一主题的重要方面的知识由此被转化和扩增”1905年罗伯特·科赫德国“对结核病的相关研究和发现”1906年卡米洛·高尔基意大利“在神经系统结构研究上的工作”圣地亚哥·拉蒙-卡哈尔西班牙1907年夏尔·路易·阿方斯·拉韦朗法国“对原生动物在致病中的作用的研究”1908年伊拉·伊里奇·梅契尼科夫俄罗斯“在免疫性研究上的工作”保罗·埃尔利希德国1909年埃米尔·特奥多尔·科赫尔瑞士“对甲状腺的生理学、病理学以及外科学上的研究”1910年阿尔布雷希特·科塞尔德国“通过对包括细胞核物质在内的蛋白质的研究，为了解细胞化学做出的贡献”1911年阿尔瓦·古尔斯特兰德瑞典“在眼睛屈光学研究上的工作”1912年亚历克西·卡雷尔法国“在血管结构以及血管和器官移植研究上的工作”1913年夏尔·罗贝尔·里歇法国“在过敏反应研究上的工作”1914年罗伯特·巴拉尼奥地利“在前庭器官的生理学与病理学研究上的工作”1919年朱尔·博尔代比利时“免疫性方面的发现”1920年奥古斯特·克罗丹麦“发现毛细血管运动的调节机理”1922年阿奇博尔德·希尔英国“在肌肉产生热量上的发现”奥托·迈尔霍夫德国“发现肌肉中氧的消耗和乳酸代谢之间的固定关系”1923年弗雷德里克·格兰特·班廷加拿大“发现胰岛素”约翰·麦克劳德加拿大1924年威廉·埃因托芬荷兰“发明心电图装置”1926年约翰尼斯·菲比格丹麦“发现鼠癌”1927年朱利叶斯·瓦格纳-尧雷格奥地利“发现在治疗麻痹性痴呆过程中疟疾接种疗法的治疗价值”1928年查尔斯·尼柯尔法国“在斑疹伤寒研究上的工作”1929年克里斯蒂安·艾克曼荷兰“发现抗神经炎的维生素”弗雷德里克·霍普金斯爵士英国“发现刺激生长的维生素”1930年卡尔·兰德施泰纳奥地利“发现人类的血型”1931年奥托·海因里希·瓦尔堡德国“发现呼吸酶的性质和作用方式”1932年查尔斯·斯科特·谢灵顿爵士英国“发现神经元的相关功能”埃德加·阿德里安英国1933年托马斯·亨特·摩尔根美国“发现遗传中染色体所起的作用”1934年乔治·惠普尔美国“发现贫血的肝脏治疗法”乔治·迈诺特美国威廉·莫菲美国1935年汉斯·斯佩曼德国“发现胚胎发育中的组织者（胚胎发育中起中心作用的胚胎区域）效应”1936年亨利·哈利特·戴尔爵士英国“神经冲动的化学传递的相关发现”奥托·勒维奥地利1937年圣捷尔吉·阿尔伯特匈牙利“与生物燃烧过程有关的发现，特别是关于维生素C和延胡索酸的催化作用”1938年海门斯比利时“发现窦和主动脉机制在呼吸调节中所起的作用”1939年格哈德·多马克德国“发现百浪多息（一种磺胺类药物）的抗菌效果”1943年亨利克·达姆丹麦“发现维生素K”爱德华·阿德尔伯特·多伊西美国“发现维生素K的化学性质”1944年约瑟夫·厄尔兰格美国“发现单神经纤维的高度分化功能”赫伯特·斯潘塞·加塞美国1945年亚历山大·弗莱明爵士英国“发现青霉素及其对各种传染病的疗效”恩斯特·伯利斯·柴恩英国霍华德·弗洛里爵士澳大利亚1946年赫尔曼·约瑟夫·马勒美国“发现用X射线辐射的方法能够产生突变”1947年卡尔·斐迪南·科里美国“发现糖原的催化转化原因”格蒂·特蕾莎·科里美国贝尔纳多·奥赛阿根廷“发现垂体前叶激素在糖代谢中的作用”1948年保罗·赫尔曼·穆勒瑞士“发现DDT是一种高效杀死多类节肢动物的接触性毒药”1949年瓦尔特·鲁道夫·赫斯瑞士“发现间脑的功能性组织对内脏活动的调节功能”安东尼奥·埃加斯·莫尼斯葡萄牙“发现前脑叶白质切除术对特定重性精神病患者的治疗效果”1950年菲利普·肖瓦特·亨奇美国“发现肾上腺皮质激素及其结构和生物效应”爱德华·卡尔文·肯德尔美国塔德乌什·赖希施泰因瑞士1951年马克斯·泰累尔南非“黄热病及其治疗方法上的发现”1952年赛尔曼·A·瓦克斯曼美国“发现链霉素，第一个有效对抗结核病的抗生素”1953年汉斯·阿道夫·克雷布斯英国“发现柠檬酸循环”弗里茨·阿尔贝特·李普曼美国“发现辅酶A及其对中间代谢的重要性”1954年约翰·富兰克林·恩德斯美国“发现脊髓灰质炎病毒在各种组织培养基中的生长能力”弗雷德里克·查普曼·罗宾斯美国韦勒美国1955年阿克塞尔·胡戈·特奥多尔·特奥雷尔瑞典“发现氧化酶的性质和作用方式”1956年安德烈·弗雷德里克·考南德美国“心脏导管术及其在循环系统的病理变化方面的发现”沃纳·福斯曼德国迪金森·伍德拉夫·理查兹美国1957年达尼埃尔·博韦意大利“发现抑制某些机体物质作用的合成化合物，特别是对血管系统和骨骼肌的作用”1958年乔治·韦尔斯·比德尔美国“发现基因功能受到特定化学过程的调控”爱德华·劳里·塔特姆美国乔舒亚·莱德伯格美国“发现细菌遗传物质的基因重组和组织”1959年阿瑟·科恩伯格美国“发现核糖核酸和脱氧核糖核酸的生物合成机制”塞韦罗·奥乔亚美国1960年弗兰克·麦克法兰·伯内特爵士澳大利亚“发现获得性免疫耐受”彼得·梅达沃英国1961年盖欧尔格·冯·贝凯希美国“发现耳蜗内刺激的物理机理”1962年佛朗西斯·克里克英国“发现核酸的分子结构及其对生物中信息传递的重要性”詹姆斯·杜威·沃森美国莫里斯·威尔金斯英国1963年约翰·卡鲁·埃克尔斯爵士澳大利亚“发现在神经细胞膜的外围和中心部位与神经兴奋和抑制有关的离子机理”艾伦·劳埃德·霍奇金英国安德鲁·赫胥黎英国1964年康拉德·布洛赫美国“发现胆固醇和脂肪酸的代谢机理和调控作用”费奥多尔·吕嫩德国1965年方斯华·贾克柏法国“在酶和病毒合成的遗传控制中的发现”安德列·利沃夫法国贾克·莫诺法国1966年裴顿·劳斯美国“发现诱导肿瘤的病毒”哈金斯美国“发现前列腺癌的激素疗法”1967年拉格纳·格拉尼特瑞典“发现眼睛的初级生理及化学视觉过程”霍尔登·凯弗·哈特兰美国乔治·沃尔德美国1968年罗伯特·W·霍利美国“破解遗传密码并阐释其在蛋白质合成中的作用”哈尔·葛宾·科拉纳美国马歇尔·沃伦·尼伦伯格美国1969年马克斯·德尔布吕克美国“发现病毒的复制机理和遗传结构”阿弗雷德·赫希美国萨尔瓦多·卢瑞亚美国1970年朱利叶斯·阿克塞尔罗德美国“发现神经末梢中的体液性传递物质及其贮存、释放和抑制机理”乌尔夫·冯·奥伊勒瑞典伯纳德·卡茨爵士英国1971年埃鲁·威尔布尔·苏德兰美国“发现激素的作用机理”1972年杰拉尔德·埃德尔曼美国“发现抗体的化学结构”罗德尼·罗伯特·波特英国1973年卡尔·冯·弗利德国“发现个体与社会性行为模式的组织和引发”康拉德·洛伦兹奥地利尼可拉斯·庭伯根英国1974年阿尔伯特·克劳德比利时“细胞的结构和功能组织方面的发现”克里斯汀·德·迪夫比利时乔治·埃米尔·帕拉德美国1975年戴维·巴尔的摩美国“发现肿瘤病毒和细胞的遗传物质之间的相互作用”罗纳托·杜尔贝科美国霍华德·马丁·特明美国1976年巴鲁克·塞缪尔·布隆伯格美国“发现传染病产生和传播的新机理”丹尼尔·卡尔顿·盖杜谢克美国1977年罗歇·吉耶曼美国“发现大脑分泌的肽类激素”安德鲁·沙利美国罗莎琳·萨斯曼·耶洛美国“开发肽类激素的放射免疫分析法”1978年沃纳·亚伯瑞士“发现限制性内切酶及其在分子遗传学方面的应用”丹尼尔·那森斯美国汉弥尔顿·史密斯美国1979年阿兰·麦克莱德·科马克美国“开发计算机辅助的断层扫描技术”高弗雷·豪斯费尔德英国1980年巴茹·贝纳塞拉夫美国“发现调节免疫反应的细胞表面受体的遗传结构”让·多塞法国乔治·斯内尔美国1981年罗杰·斯佩里美国“发现大脑半球的功能性分工”大卫·休伯尔美国“发现视觉系统的信息加工”托斯坦·维厄瑟尔瑞典1982年苏恩·伯格斯特龙瑞典“发现前列腺素及其相关的生物活性物质”本格特·萨米尔松瑞典约翰·范恩英国1983年巴巴拉·麦克林托克美国“发现可移动的遗传元素”1984年尼尔斯·杰尼丹麦“关于免疫系统的发育和控制特异性的理论，以及发现单克隆抗体产生的原理”乔治斯·克勒德国色萨·米尔斯坦英国1985年麦可·布朗美国“在胆固醇代谢的调控方面的发现”约瑟夫·里欧纳德·戈尔茨坦美国1986年斯坦利·科恩美国“发现生长因子”丽塔·列维-蒙塔尔奇尼美国1987年利根川进日本“发现抗体多样性产生的遗传学原理”1988年詹姆士·W·布拉克爵士英国“发现药物治疗的重要原理”格特鲁德·B·埃利恩美国乔治·希青斯美国1989年迈克尔·毕晓普美国“发现逆转录病毒致癌基因的细胞来源”哈罗德·瓦慕斯美国1990年约瑟夫·默里美国“发明应用于人类疾病治疗的器官和细胞移植术”唐纳尔·托马斯美国1991年厄温·内尔德国“发现细胞中单离子通道的功能”伯特·萨克曼德国1992年埃德蒙·费希尔美国“发现的可逆的蛋白质磷酸化作用是一种生物调节机制”埃德温·克雷布斯美国1993年理察·罗伯茨英国“发现断裂基因”菲利普·夏普美国1994年艾尔佛列·古曼·吉尔曼美国“发现G蛋白及其在细胞中的信号转导作用”马丁·罗德贝尔美国1995年爱德华·路易斯美国“发现早期胚胎发育中的遗传调控机理”克里斯汀·纽斯林-沃尔哈德德国艾瑞克·威斯乔斯美国1996年彼得·杜赫提澳大利亚“发现细胞介导的免疫防御特性”罗夫·辛克纳吉瑞士1997年史坦利·布鲁希纳美国“发现朊病毒——传染的一种新的生物学原理”1998年罗伯·佛契哥特美国“发现在心血管系统中起信号分子作用的一氧化氮”路易斯·路伊格纳洛美国费瑞·慕拉德美国1999年古特·布洛伯尔美国“发现蛋白质具有内在信号以控制其在细胞内的传递和定位”2000年阿尔维德·卡尔森瑞典“发现神经系统中的信号传导”保罗·格林加德美国艾瑞克·坎德尔美国2001年利兰·哈特韦尔美国“发现细胞周期的关键调节因子”蒂姆·亨特英国保罗·纳斯爵士英国2002年悉尼·布伦纳英国“发现器官发育和细胞程序性死亡的遗传H·罗伯特·霍维茨美国调控机理”约翰·E·苏尔斯顿美国2003年保罗·劳特伯美国“在核磁共振成像方面的发现”彼得·曼斯菲尔德爵士英国2004年理查德·阿克塞尔美国“发现嗅觉受体和嗅觉系统的组织方式”琳达·巴克美国2005年巴里·马歇尔澳大利亚“发现幽门螺杆菌及其在胃炎和胃溃疡中所起的作用”罗宾·沃伦澳大利亚2006年安德鲁·法厄美国“发现了RNA干扰——双链RNA引发的沉默现象”克雷格·梅洛美国2007年马里奥·卡佩奇美国“在利用胚胎干细胞引入特异性基因修饰的原理上的发现”马丁·埃文斯爵士英国奥利弗·史密斯美国2008年哈拉尔德·楚尔·豪森德国“发现了导致子宫颈癌的人乳头状瘤病毒”弗朗索瓦丝·巴尔-西诺西法国“发现人类免疫缺陷病毒（即艾滋病病毒）”吕克·蒙塔尼法国2009年伊丽莎白·布莱克本澳大利亚“发现端粒和端粒酶如何保护染色体”卡罗尔·格雷德美国杰克·绍斯塔克英国2010年罗伯特·杰弗里·爱德华兹英国“因为在试管婴儿方面的研究获奖”2011年布鲁斯·巴特勒美国"他们对于先天免疫机制激活的发现"朱尔斯·霍尔曼法国拉尔夫·斯坦曼美国"他发现树突状细胞和其在后天免疫中的作用"2012年约翰·格登爵士英国“发现成熟细胞可被重写成多功能细胞”[2]山中伸弥日本2013年詹姆斯·E·罗斯曼美国细胞囊泡交通的运行与调节机制兰迪-W.谢克曼托马斯-C.苏德霍夫德国2014年John O'Keefe(约翰-欧基夫) 美国发现了大脑中形成定位系统的细胞May Britt Moser(梅-布莱特-莫索尔) 挪威Edvand Moser(爱德华-莫索尔) 挪威。

2014年诺贝尔生理学或医学奖：在大脑中内置的“GPS”我们如何知道自己的位置？我们如何从一个地方去到另一个地方？为何当我们在下次重复同样的路线时能够迅速查找到这些信息，我们在大脑中是如何对它们进行存储的？今年的诺贝尔生理学或医学奖获得者们发现了大脑内的定位系统，大脑中一种内置的“GPS”，它让我们能够在空间中实现定位，揭示了高等认知能力的细胞层面机制。

1971年，约翰・奥基夫发现了构成这一体系的第一个组成部分。

他在大脑一个名叫“海马体”的区域发现了一种特殊的神经细胞，当实验小鼠在房间内的某一特定位置时其中一部分这样的细胞总是显示激活状态。

而当小鼠在房间内的其他位置时，另外一些细胞则显示激活状态。

奥基夫认为这些是“位置细胞”，它们构成了小鼠对所在房间的地图。

30多年后，在2005年，梅・布莱特・莫索尔和爱德华・莫索尔夫妇发现大脑定位机制的另外一项关键组成部分。

他们识别出另外一种神经细胞，他们将其称之为“网格细胞”，这些细胞产生一种坐标体系，从而让精确定位与路径搜寻成为可能。

他们随后进行的研究揭示了位置细胞以及网格细胞是如何让定位与导航成为可能的。

约翰・奥基夫以及梅・布莱特・莫索尔和爱德华・莫索尔夫妇的发现解答了一个困扰哲学家和科学家们长达数个世纪的谜团―大脑究竟如何创建一个有关自身周围空间位置的地图？我们又究竟如何能够在复杂的环境中找到方向？对位置的感知以及判断方向的能力是我们生存的基础。

对位置的感知构成我们在环境中对自身所处地点的知觉。

而在行进的过程中，我们将基于运动状态给出的距离判断与有关先前位置的信息结合了起来。

有关位置与路径寻找的问题长期以来困扰着哲学家和科学家们。

200多年前，德国哲学家康德提出我们拥有一些所谓“先验知识”，它们独立于人的经验而存在。

他将空间的概念视为思维的内在属性之一，这是我们感知世界的唯一的方式。

随着20世纪中叶行为心理学的发展，人们开始用试验方法探究这些问题的答案。

2014年诺贝尔生理医学奖获得者科研方法初探摘要】约翰?奥基夫、梅?布里特?莫泽和爱德华?莫泽获得了2014年诺贝尔生理学或医学奖。

系统探讨他们的科学研究经历，归纳总结他们的科学研究方法：传习继承法、创新思维法、实验验证法、多学科交叉法。

他们的科研方法对提高我们中医院校大学生的创新思维和创新能力具有重要的参考价值。

【关键词】诺贝尔生理医学奖约翰?奥基夫位置细胞科研方法【中图分类号】R39 【文献标识码】A 【文章编号】2095-1752（2014）22-0119-02一、前言2014年10月6日17:30， 2014年诺贝尔生理学或医学奖的评选结果在斯德哥尔摩宣布，爱尔兰裔美国暨英国籍神经科学家约翰?奥基夫、挪威的心理学家、神经科学家梅?布里特?莫泽和爱德华?莫泽被授予诺奖，以表彰他们发现大脑定位系统细胞的研究。

20世纪70年代，奥基夫于小鼠大脑的海马体区域发现了一种特殊的神经细胞，他将其命名为“位置细胞”。

海马体，顾名思义，是形状与海马相似的大脑的一个组成部分，具有负责人们记忆和学习的功能。

一直以来，科学家们通过不懈的探索，发现了它在储存记忆方面的作用，而奥基夫创新性地发现了它在空间定位方面的作用。

同时奥基夫的研究也使莫泽夫妇受到启发，莫泽夫妇发现了存在于内嗅皮层的网格细胞，稳定的网格结构有助于大脑形成空间动态，动物的大脑中确实存在着类似于空间坐标系的建立机制。

奥基夫、莫泽夫妇以及其它领域的科学家很快建立起一套全新的理论模型，并不同于导向细胞之间的相互协作，它为人们深入理解学习记忆机制与诊断脑功能障碍的相关病症带来了福音。

二、约翰?奥基夫与莫泽夫妇的科研方法1.继承：站在前人的肩膀上我们身处何处？我们从哪里来？又该往哪里去？关于地点位置和导航的问题一直是困扰着人们的大谜团。

早在200多年前，德国哲学家康德就认为时间和空间是感性的先天形式，即时间和空间是作为认识主体的人先天具有的感知世界的认识形式和工具。

身在何处--2014年诺贝尔生理学或医学奖介绍
汪云九
【期刊名称】《自然杂志》
【年(卷),期】2014(000)006
【摘要】首先简要介绍2014年诺贝尔生理学或医学奖三位获奖者(John M. O’Keefe，Edvard I. Moser 和 May-Britt Moser)的学术生涯。

然后详细介绍他们获奖的主要成就：O’keefe教授在20世纪70年代发现鼠海马上神经细胞对动物所处的位置敏感，因此命名为位置细胞；而后Moser夫妇在鼠脑的内嗅皮质中发现栅格细胞，它的感受野呈现有规律的三角形网格覆盖整个环境，从而认为这些细胞组织成动物导航系统的神经机制具有可能性。

最后指出，由于脑科学研究的复杂性，这些研究工作仅是动物导航行为探究中的重大突破，离开彻底解决这个问题尚有距离。

【总页数】6页(P409-414)
【作者】汪云九
【作者单位】中国科学院生物物理研究所脑与认知科学国家重点实验室，北京100101
【正文语种】中文
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1.2014年诺贝尔生理学或医学奖获得者的科学方法研究 [J], 杨丽;张洪雷
2.大脑定位系统是怎样构成的——2014年诺贝尔生理学或医学奖工作介绍 [J], 宋伟
3.诺贝尔奖工作回顾细胞凋亡的分子机制及其在当前医学中的应用——2002年诺贝尔生理学或医学奖工作介绍及研究进展 [J], 宋伟;宋德懋
4.空间在大脑中的表征--2014年诺贝尔生理学或医学奖解读 [J], 郭超
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