记忆存储的秘密

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; m( ]! ?6 G( N1 G' Q) i2 [http://www.sciencedaily.com/releases/2015/05/150528142815.htm9 B9 U+ x7 _# r, e; q9 h
Memories that have been "lost" as a result of amnesia can be recalled by activating brain cells with light.
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In a paper published today in the journal Science, researchers at MIT reveal that they were able to reactivate memories that could not otherwise be retrieved, using a technology known as optogenetics.7 v2 ~  h" {( T1 K, P

0 [$ p! a( z9 Q; uThe finding answers a fiercely debated question in neuroscience as to the nature of amnesia, according to Susumu Tonegawa, the Picower Professor in MIT's Department of Biology and director of the RIKEN-MIT Center at the Picower Institute for Learning and Memory, who directed the research by lead authors Tomas Ryan, Dheeraj Roy, and Michelle Pignatelli.
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Neuroscience researchers have for many years debated whether retrograde amnesia -- which follows traumatic injury, stress, or diseases such as Alzheimer's -- is caused by damage to specific brain cells, meaning a memory cannot be stored, or if access to that memory is somehow blocked, preventing its recall., o% o) h4 u. h0 r, F  V  {9 }
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"The majority of researchers have favored the storage theory, but we have shown in this paper that this majority theory is probably wrong," Tonegawa says. "Amnesia is a problem of retrieval impairment."
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0 |5 I" w: G7 EMemory researchers have previously speculated that somewhere in the brain network is a population of neurons that are activated during the process of acquiring a memory, causing enduring physical or chemical changes.
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9 M; v, q2 o8 ?8 k7 c2 mIf these groups of neurons are subsequently reactivated by a trigger such as a particular sight or smell, for example, the entire memory is recalled. These neurons are known as "memory engram cells."& Q. s% S, E1 V; _# \
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Shedding light4 e9 ^, r1 d8 u

6 l  Q0 I, F, v1 g  N; A9 }In 2012 Tonegawa's group used optogenetics -- in which proteins are added to neurons to allow them to be activated with light -- to demonstrate for the first time that such a population of neurons does indeed exist in an area of the brain called the hippocampus.
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However, until now no one has been able to show that these groups of neurons do undergo enduring chemical changes, in a process known as memory consolidation. One such change, known as "long-term potentiation" (LTP), involves the strengthening of synapses, the structures that allow groups of neurons to send signals to each other, as a result of learning and experience.) y4 y; h0 M  X7 i2 y! U; T# `1 R
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To find out if these chemical changes do indeed take place, the researchers first identified a group of engram cells in the hippocampus that, when activated using optogenetic tools, were able to express a memory.+ o; @& x5 [$ F4 R3 ]$ e8 r! i5 v
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When they then recorded the activity of this particular group of cells, they found that the synapses connecting them had been strengthened. "We were able to demonstrate for the first time that these specific cells -- a small group of cells in the hippocampus -- had undergone this augmentation of synaptic strength," Tonegawa says.6 Q2 n5 X- p& z, R* `# p6 J6 s

) n: D# X6 K+ x0 v. c/ x5 ^The researchers then attempted to discover what happens to memories without this consolidation process. By administering a compound called anisomycin, which blocks protein synthesis within neurons, immediately after mice had formed a new memory, the researchers were able to prevent the synapses from strengthening.8 {/ r2 m% P* Q# _$ _
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When they returned one day later and attempted to reactivate the memory using an emotional trigger, they could find no trace of it. "So even though the engram cells are there, without protein synthesis those cell synapses are not strengthened, and the memory is lost," Tonegawa says.# D& N, D( w1 I2 g

! u3 E( X8 R: T0 V* g: KBut startlingly, when the researchers then reactivated the protein synthesis-blocked engram cells using optogenetic tools, they found that the mice exhibited all the signs of recalling the memory in full.& p6 f  D$ J/ a8 w3 g, I

* @  \2 T8 E, T"If you test memory recall with natural recall triggers in an anisomycin-treated animal, it will be amnesiac, you cannot induce memory recall," Tonegawa says. "But if you go directly to the putative engram-bearing cells and activate them with light, you can restore the memory, despite the fact that there has been no LTP."
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& B: O8 n8 r# b: G* N0 U8 N, F"Groundbreaking paper"0 [6 Y7 \1 n4 O) J5 ?4 Z. [# N
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Further studies carried out by Tonegawa's group demonstrated that memories are stored not in synapses strengthened by protein synthesis in individual engram cells, but in a circuit, or "pathway" of multiple groups of engram cells and the connections between them.3 t, f/ b8 I% {3 V4 y, l5 ^$ `
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"We are proposing a new concept, in which there is an engram cell ensemble pathway, or circuit, for each memory," he says. "This circuit encompasses multiple brain areas and the engram cell ensembles in these areas are connected specifically for a particular memory.": N: a5 |$ Q, {  N6 y, Z. y7 S

! f1 ]7 G# Q7 i9 O9 J, f# tThe research dissociates the mechanisms used in memory storage from those of memory retrieval, according to Ryan. "The strengthening of engram synapses is crucial for the brain's ability to access or retrieve those specific memories, while the connectivity pathways between engram cells allows the encoding and storage of the memory information itself," he says.
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3 w& U$ M) r! s9 O9 f, h8 iChanges in synaptic strength and in spine properties have long been associated with learning and memory, according to Alcino Silva, director of the Integrative Center for Learning and Memory at the University of California at Los Angeles. "This groundbreaking paper suggests that these changes may not be as critical for memory as once thought, since under certain conditions, it seems to be possible to disrupt these changes and still preserve memory," he says. "Instead, it appears that these changes may be needed for memory retrieval, a mysterious process that has so far evaded neuroscientists."
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9 w) s+ u* t3 D3 ], d# I" bStory Source:
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The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Helen Knight. Note: Materials may be edited for content and length.
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! `8 a: ^6 ]# N6 yJournal Reference:
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Tomás J. Ryan, Dheeraj S. Roy, Michele Pignatelli, Autumn Arons, and Susumu Tonegawa. Engram cells retain memory under retrograde amnesia. Science, 29 May 2015: 1007-1013 DOI: 10.1126/science.aaa5542& ^/ g6 a# Z2 X8 j/ H* s6 b
遗忘症丢失的记忆可以通过光激活脑细胞恢复  `+ @& w( O% p. b

+ o* B& G" ~; T& g4 JTomás J. Ryan, Dheeraj S. Roy, Michele Pignatelli, Autumn Arons, and Susumu Tonegawa. Engram cells retain memory under retrograde amnesia. Science, 29 May 2015: 1007-1013 DOI: 10.1126/science.aaa55420 Z  z' j+ v0 [% k8 @2 C

$ [/ w+ a& X  q近期MIT的研究者在science上发表了一篇文章，文章中他们使用optogenetics（光遗传学技术）重新恢复实验鼠丢失的记忆。
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- w6 m" A2 ~: N% J0 ^Susumu Tonegawa, the Picower Professor in MIT's Department of Biology and director of the RIKEN-MIT Center at the Picower Institute for Learning and Memory 带领了Tomas Ryan, Dheeraj Roy 和 Michelle Pignatelli 完成了这项研究，这一研究解答了神经领域一个具有争议性的问题，即遗忘症的本质是什么？1 u5 M( A7 C9 L2 l5 d; K- A8 U# D
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神经科学研究者多年来都在争论是否可以逆转遗忘症，遗忘症主要是由外伤，压力或阿尔茨海默氏症等疾病导致的特定脑细胞损伤引起的，这意味着记忆不能被存储或者访问记忆的途径被切断导致记忆无法恢复。  [0 Z* e  Y& z

4 `; X6 O, `/ U" b/ X1 b6 ?3 |6 f利根川进说：“大多数研究人员都青睐于存储理论（即细胞损伤记忆无法储存），但我们已经在我们的论文中证明，这个理论可能是错误的，即失忆是检索障碍导致的问题。”（这两个问题不一定是矛盾的呀，有可能都存在呀？皮质不存,毛将焉附）
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记忆研究者根据以前的研究推测大脑某处神经元细胞在产生记忆时被激活，产生持久性的物理或化学变化。举例来说，当这些神经元被特定的视觉或气味信号刺激后重新激活，整个记忆被重新调出，这些神经元被称为“ memory engram cells记忆印迹细胞”。
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6 W+ P" @) z5 u' ^) `+ S在2012年利根川的小组利用光遗传学（在神经元细胞中人为地加入可以被光激活的蛋白）证明了这群细胞的确存在于大脑中的海马区。: A! b- Q' @; {$ W
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然而，直到现在也没有研究者证明在记忆巩固过程中这些细胞确实发生了持久性的化学变化。其中一种化学变化被称为“长期增强作用”（LTP），涉及到在学习和经验积累过程中突触连接的加强（突触是神经元之间联系的桥梁，允许神经元彼此之间发送信号）。
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9 f% l. X% h5 f8 p# y# e为了证明这些化学变化确实发生，研究人员使用optogenetic 光遗传学工具首先发现了海马区的一群细胞（印迹细胞）能够在光激活后产生记忆。然后他们记录这些细胞的活动，发现它们之间的突触连接加强了。 利根川进说：“我们第一次证明了这群海马中的特定的细胞经历了突触连接增强的变化。”9 p% W/ g/ z; A2 N+ P' i$ |

, @0 i7 V1 q# y* C5 \9 B然后，研究人员试图了解如果这一反应无法正常进行，记忆的产生过程会发生什么变化。研究者将一种叫做anisomycin茴香化合物注入到神经元中阻止蛋白质合成，这样产生记忆时神经元之间的突触连接无法加强。
, b% L2 D& z% S# \当他们第二天试图用情感触发来重新激活记忆时，他们发现这段记忆消失了。利根川进说：“因此即使印迹细胞都还在，没有蛋白质合成导致细胞突触连接无法加强，记忆丢失了。”# s3 J& b* j4 ^2 G9 C

9 ^' K# `' _5 ]! G! D9 T9 h但令人吃惊，当研究人员使用 optogenetic 光遗传学工具激活蛋白质合成受阻的印迹细胞，小鼠表现出恢复记忆的迹象。（这个确实很奇怪，要想一想才行，记忆的储存形式是什么？）
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6 B$ u" ^6 f* T: Q5 A  f7 Q, l利根川进说：“如果你使用自然触发条件去诱导anisomycin处理的小鼠，小鼠遗忘了记忆，你无法诱导记忆的恢复。但是如果直接使用光激活印迹细胞，就可以恢复记忆，虽然这个过程并没有 LTP。”
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这是开创性的论文。1 @& }6 n0 J" ]4 i" @

  k+ G6 O/ Y" _' }利根川领导的研究团队开展了进一步的研究，他们发现记忆存储不是由单个印迹细胞通过蛋白合成强化突触连接完成的，这是由一个细胞网络产生的，即多个组印迹细胞产生的“通路”和它们之间的连接构成了记忆。7 ]  A4 o; T: W. p$ \( M9 U5 h

0 s( p6 Z9 A; i. D) x9 J" p他说：“我们提出了一个新的概念，一个印迹细胞群或者说网络是记忆的本质。这个细胞网络跨越大脑的很多区域，特定的网络连接产生特定的记忆。”
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Ryan表示他们通过对记忆的恢复的研究了解了记忆存储的机制。他说：“印迹细胞突触的加强对于访问或检索特定记忆是至关重要，印迹细胞通过产生连接来编码和存储记忆信息。”' @) H$ y1 V7 @- ~* V( r9 ?
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Alcino Silva, director of the Integrative Center for Learning and Memory at the University of California at Los Angeles表示改变突触连接的强度和脊柱性能（？）一直被认为与学习和记忆有关。他说：“这一突破性论文的表明这些变化对于记忆产生可能没有想象中重要，因为在某些情况下，破坏这些改变还是可以储存记忆，相反，这些变化可能对于记忆的检索和提取是非常重要的，迄今为止这对于神经学家来说还是个未知的领域。”