2014 生物醫(yī)學獎

1、2014 諾貝爾生物醫(yī)學獎摘要：2014年諾貝爾生理學或醫(yī)學獎頒發(fā)給美國和英國國籍科學家約翰·奧基夫（John OKeefe）及兩位挪威籍科學家梅-布里特·莫澤（May-Britt Moser）和愛德華·莫澤（Edvard I. Moser），表彰他們發(fā)現了大腦中的“內置GPS（global positioning system）”定位系統(tǒng)的細胞學機制。 更多還原關鍵字：約翰·奧基夫（John OKeefe）梅-布里特·莫澤（May-Britt Moser）愛德華·莫澤（Edvard I. Moser），大腦中的“內置GPS

2、（global positioning system，海馬區(qū)，定位， 。2014年諾貝爾生理學或醫(yī)學獎被授予約翰·奧基夫（John O Keefe）、邁-布里特·莫澤（MayBritt Moser）和愛德華·莫澤（ Edvard Moser）三人。他們發(fā)現了大腦里的“GPS”系統(tǒng)。圖片來我們是怎么知道我們身在何方的？我們怎么找到從一個地方到另一個地方的路線的？我們是怎么把這些信息儲存下來，讓我們重返故地的時候能立刻找到路？2014年諾貝爾生理學或醫(yī)學獎的得獎者發(fā)現了大腦里的“定位系統(tǒng)”，一臺內置的GPS，使得我們能在空間中定位自己身在何處，這表明這種高級認知功能也

3、有細胞級別的基礎。1971年，約翰·奧基夫發(fā)現了這個定位系統(tǒng)的第一個成分。他發(fā)現，大腦海馬體里有一種神經細胞，每當大鼠身處屋子的某個特定地點的時候，這種細胞總是會被激活。其它神經細胞則在大鼠身處其它地方的時候被激活。奧基夫的結論是，這些“位置細胞”（place cells）組成了屋子的地圖。三十多年后，邁-布里特·莫澤和愛德華·莫澤發(fā)現了大腦定位系統(tǒng)的另一個關鍵成分。他們發(fā)現了另一種神經細胞，命名為“網格細胞”（grid cells），它們組成了一個坐標系，允許生物進行精確的定位和尋路。他們的后續(xù)研究表明，地點細胞和網格細胞一起使得定位和導航成為可能。約翰

4、3;奧基夫，邁-布里特·莫澤和愛德華·莫澤的研究回答了困擾哲學家和科學家數百年的問題大腦如何給周圍的空間創(chuàng)造地圖，我們如何在復雜的環(huán)境中尋找路線 在20世紀60年代晚期，約翰·奧基夫對于大腦如何控制行為和決策這一問題十分著迷，并常試圖用神經生理學的方式來解決這一問題。當他記錄在屋內自由跑動的大鼠的大腦海馬體內單個神經細胞的信號時，奧基夫發(fā)現，當大鼠經過特定位置時，某些神經細胞會被激活。他發(fā)現這些“位置細胞”不僅僅接受視覺信號輸入，而且還會在腦中繪制周圍環(huán)境的地圖。奧基夫總結道，通過在不同環(huán)境中被激活的不同的位置細胞，海馬體能生成很多地圖。因此，關于環(huán)境的記憶能以位

5、置細胞活性的特定組合形式被存在海馬體中。邁-布里特·莫澤和愛德華·莫澤找到了定位系統(tǒng) 邁-布里特·莫澤和愛德華·莫澤在繪制移動中的大鼠的海馬體連接時，在附近的內嗅皮層中發(fā)現了一種讓人驚異的活動模式。當小鼠通過六角網格中的某些位置時，內嗅皮層中的某些固定的細胞會被激活。每個細胞都對應著某個特定的空間格局，這些“網格細胞”共同建立出一個可以進行空間導航的坐標系統(tǒng)。它們和內嗅皮層中其他負責辨識頭部方向和房間邊界的細胞一起，與海馬體中的位置細胞共同組成了神經回路。這個回路系統(tǒng)在大腦中建立了一套宗合定位系統(tǒng)，一個內置的GPS。 人類大腦里的“地圖”根據最近的腦成像

6、技術調查，以及對接受神經外科手術患者的研究都顯示，位置細胞同樣存在于人體中。在早期階段阿爾茲海默氏疾病的早期階段，患者的海馬體和內嗅皮質經常會受到影響，以致這些患者經常無法辨別周邊環(huán)境并且迷路。了解大腦的位置系統(tǒng)或許可以因此幫助我們了解這種疾病如何對患者的空間記憶喪失造成影響。這一對大腦位置系統(tǒng)的發(fā)現代表了我們進一步認識大腦特化細胞如何協(xié)同合作，并執(zhí)行更高水平的認知功能。它為我們理解認知過程，比如記憶、思維與計劃開辟了新的途徑?？臻g認知領域里程碑式的發(fā)現“實至名歸?！北本┐髮W神經科學研究所研究員伊鳴談及此次獲獎成果難掩興奮。作為獲獎者約翰·奧基夫的學生，他曾在英國倫敦大學學院解剖與發(fā)

7、育生物學系神經科學專業(yè)學習了5年半，研究領域正是小鼠海馬神經網絡動力學變化及其與動物病理學及行為學變化的相關性。為了讓記者更好地理解3位科學家對于空間認知發(fā)展的巨大貢獻，伊鳴拿出了其所講授的研究生課程PPT，為記者上了生動一課?！翱茖W界對空間認知的研究，可以追溯到上世紀30年代40年代。當時，全球認知心理學領域頂級專家Lashley提出了刺激反應模型，從心理學角度對空間認知進行了解釋，其基本理論是個體對于空間認知的過程來自于對視覺、聽覺等各種不同刺激的累積反應。然而，幾年后，這一當時被奉為圭臬的假說，被一系列的動物實驗推翻了。1948年，愛德華·托爾曼又提出了“認知地圖”的概念，即空

8、間認知過程不是單純的刺激反應，而是大腦某些地方可以通過編寫地圖告訴個體自身位置?？上У氖?，這一假說一直沒有得到證實。直到1957年，世界上首個切除雙側海馬腦區(qū)以治療嚴重癲癇的病例被報道，患者術后失去了形成新的長時間記憶的能力，空間認知也出現了障礙，這些變化首次證實了“認知地圖”可能真的存在，而且存在部位可能在海馬腦區(qū)。此后，全球神經解剖學、生理學、行為學等不同領域的科學家都把研究重心放在了海馬腦區(qū)，嘗試回答這一腦區(qū)參與認知過程的機制，但一直未能獲得成功。直到1971年，約翰·奧基夫發(fā)現了海馬腦區(qū)的“位置細胞”。伊鳴為記者播放了一段視頻。視頻還原了奧基夫的實驗：大鼠在一個箱子里自由活動

9、，電極被埋置在大鼠海馬腦區(qū)，大鼠在活動中，每經過一個特定區(qū)域，一個海馬神經元（位置細胞）就會開始發(fā)放動作電位，與此同時，記錄神經元放電的設備閃爍燈光，并發(fā)出“呲呲”的放電聲音。1978年，奧基夫等人編寫了海馬是一個認知地圖一書，第一次比較完整系統(tǒng)地闡述了海馬腦區(qū)的功能，以及空間認知行為機制。在此基礎上，莫澤夫婦于2005年在海馬腦區(qū)上游的“內嗅皮層”區(qū)域發(fā)現了“網格細胞”，當小鼠運動不同距離時，特定的神經元會被激活，當內嗅皮層上百萬神經元放電情況累計后，小鼠就可以對自己的運動軌跡進行判斷?！皬臄祵W模型角度來說，個體定位自身位置有兩個重要因素，一是方向，二是距離，因此，當這兩個關鍵因素的細胞機制

10、被揭示后，空間認知過程中最核心的問題也得到了解決?！币柳Q表示，此后，莫澤夫婦又陸續(xù)發(fā)現嗅腦其他細胞能夠同時判斷距離和方向，以及環(huán)境的“邊界”，而上述細胞與“位置細胞”構成一條完整的回路。這一回路系統(tǒng)構成了一個復雜的定位體系，大腦內置“GPS”的運轉機制被揭示。成功來自思想創(chuàng)新和科學理想“在空間認知領域，有一個固定短語，叫奧基夫試驗，意味著對于實驗設計的推崇。”在采訪中，有專家告訴記者，奧基夫的研究中最顯著的特點就是，依靠巧妙的實驗設計，結合一些基本的實驗技術，回答最關鍵的科學問題。“這與一些科學家，更多依賴新興技術進行研究完全不同?！薄?971年直接導致他獲獎的工作就是最好的例子。”據介紹，1

11、957年1971年，全球神經科學家?guī)缀醵荚谧鐾患?，就是把電極放在小鼠的海馬腦區(qū)，探索這一區(qū)域如何編碼空間記憶。然而，14年間都沒有人給出答案。與其他科學家相比，奧基夫只是對實驗設計進行革新，便改寫了歷史?！爸翱茖W家都是找一個小箱子，把老鼠放進去，然后不斷進行光、電、熱等刺激，希望找到與刺激相對應的神經元改變。但沒有人能夠做出結果。雖然奧基夫也應用相同的電生理技術，但他只是把小鼠放在一個大箱子里，讓小鼠自由活動，從而觀察某些神經元放電的時候，老鼠在干什么?！辈粌H如此，奧基夫在上世紀90年代就提出了一系列假說，即在大腦的某個地方，可能存在一些其他類型的神經元，不僅能編碼距離、邊界，還能夠同時

12、編碼方向和距離，而其中很多核心理論都被之后的研究證實了。神經科學研究是一片“藍?！痹诳茖W界，對于此次諾貝爾生理學或醫(yī)學獎的歸屬有不同聲音。對此，伊鳴分析稱，之所以有爭議，可能是因為3位科學家對于空間認知的發(fā)現更多只是解釋機制，還沒有解決臨床問題。此外，獲獎成果更多針對空間行為和空間探索，相比于DNA雙螺旋結構被發(fā)現等一些改變生物學進程的科學成果，影響范圍確實比較局限“但不能否認，3位科學家的研究成果，確實是整個認知科學領域最重要的發(fā)現。而包括空間認知在內的神經科學研究的終極目標，就是回答精神活動的生物學基礎?！币柳Q說。軍事醫(yī)學科學院基礎醫(yī)學研究所神經生物學研究室研究員劉少君表示，神經科學涉及學

13、習、記憶、認知、決策、語言、情感等多種高級腦活動，又與運動、感覺、內臟調節(jié)等個體的生存密切關聯(lián)。不僅如此，神經科學研究還包含了神經系統(tǒng)疾病的發(fā)生和治療，腦和脊髓創(chuàng)傷的修復，以及上述腦功能相關神經環(huán)路等。神經科學是當今最復雜的研究領域，也是最具突破前景的科學領域。從1901年設立諾貝爾獎至今的114年間，已有25個年度授予了48位神經科學家；而今年，諾貝爾獎又第一次授予大腦空間認知領域研究。“當前一些基于動物研究的核心理論已經在人類身上被證實，例如，近期采用大腦成像技術研究以及對接受神經外科手術的患者進行的研究表明，位置細胞與網格細胞同樣存在于人類大腦中。因此，對于大腦定位系統(tǒng)的了解或許會幫助我

14、們理解某些疾病中空間記憶缺失的具體機制?！币柳Q說，但客觀而言，要真正將理論轉化為技術，還有一段路要走。How 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? This year's Nobel Laureates have disco

15、vered 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

16、 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'Keefe concluded that these “place cells" formed a map of the room.More than three decades later, in 2005, May

17、-Britt and Edvard Moser discovered another key component of the brain's positioning system. They identified another type of nerve cell, which they called “grid cells", that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how p

18、lace 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 w

19、e 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 t

20、hat 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 experi

21、ence. 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 la

22、byrinths, 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 fascinate

23、d 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

24、 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

25、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-

26、Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room 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

27、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 bor

28、der 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 und

29、ergoing 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. Kno

30、wledge 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 ensemble

31、s 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 ev

32、idence from unit activity in the freelymoving 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 entorhina

33、l 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

34、representation of position, direction, and velocity in the entorhinal cortex. Science 312, 758-762.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

35、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

36、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 postdoctora

37、l 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

38、 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 coLaureate MayBritt Moser, first at the University of Edinburgh and later a