生物谷報道：你是怎么記住自己名字的,？是否有可能忘記它？這種記憶的痕跡似乎永久鐫刻在大腦中，不可能忘懷,。目前,，對于長期記憶的觀點是，從分子水平看,，產(chǎn)生了新蛋白質(zhì),，也即蛋白質(zhì)的翻譯過程。是這些新合成的蛋白質(zhì)保存了記憶,。也就是說,，每個新記憶都在腦中對應(yīng)著相應(yīng)的蛋白質(zhì)。但美國西北大學(xué)神經(jīng)學(xué)家羅特勃格及其博士生杰羅米-里卡特在《神經(jīng)病學(xué)》2005年1月刊上載文提出了新觀點,，對上述傳統(tǒng)觀點提出了挑戰(zhàn),。
羅特勃格說，除永久記憶外,，大腦中還有種“動態(tài)的,、亞穩(wěn)定”記憶過程。憑主觀經(jīng)驗,，人們一直認(rèn)為永久記憶是記憶通過許多大腦神經(jīng)網(wǎng)絡(luò)反復(fù)加強的結(jié)果,。比如，我們自己的名字存在于數(shù)不清的神經(jīng)回路中,，很難遺忘,。但每個神經(jīng)回路都具有可塑性，也不可能終生存在,，所以從理論上講人可能忘掉自己的名字,。這在嚴(yán)重的阿爾茨海默癥患者身上已經(jīng)得到驗證。這種不穩(wěn)定的記憶機制有很大適應(yīng)性,，即使在少數(shù)情況下發(fā)生錯誤也可得到迅速補救,，這相比永久記憶，優(yōu)越性顯而易見,。
為解釋記憶的高度適應(yīng)性,，羅特勃格的新觀點認(rèn)為學(xué)習(xí)過程激活了某些神經(jīng)突觸，需要儲存長期記憶時,，大腦迅速改變其中某些蛋白質(zhì)的構(gòu)型,。這挑戰(zhàn)了已被人們接受了40年的傳統(tǒng)理論：新合成的蛋白質(zhì)被運送到最近激活的突觸后，保存了長期記憶,。事實上,，上述傳統(tǒng)觀點是艾里克-坎德爾理論的核心，他因此曾獲得諾貝爾獎金,。
那么,，記憶究竟是象大多數(shù)學(xué)者認(rèn)為的那樣，基于蛋白質(zhì)的合成,，還是如新觀點所言,，是已有蛋白質(zhì)構(gòu)型的改變,？至少傳統(tǒng)觀點有嚴(yán)重缺陷，有足夠事實證明沒有蛋白質(zhì)合成,，一樣能保存記憶,。羅特勃格指出，傳統(tǒng)觀點的主要證據(jù)來源于對蛋白合成抑制劑的研究,，但這些研究結(jié)果值得商榷,。例如，足以阻斷90％蛋白質(zhì)合成的蛋白合成抑制劑通常不對記憶造成損害,，而其非蛋白合成抑制的副作用卻可造成記憶丟失,。
羅特勃格同意一百年前關(guān)于學(xué)習(xí)激活神經(jīng)突觸的理論。但他不同意目前有關(guān)這種激活是基于新合成蛋白質(zhì)的說法,。根據(jù)大量基礎(chǔ)生物化學(xué)過程研究,，他認(rèn)為學(xué)習(xí)引起突觸已有蛋白質(zhì)的構(gòu)型修飾，這種構(gòu)型修飾是保存長期記憶的唯一機理,。為進一步解釋構(gòu)型修飾,，羅特勃格認(rèn)為大腦平時實際上不斷地“秘密復(fù)習(xí)”著過去的體驗。長期記憶的形成有賴于這種正反饋復(fù)習(xí)機制,，在這種機制下不斷更新或微調(diào)著已有蛋白質(zhì)的構(gòu)型,。細胞內(nèi)的蛋白質(zhì)合成后修飾、突觸間信息傳遞和神經(jīng)細胞,、神經(jīng)網(wǎng)絡(luò)間的和諧互動是維持永久記憶的關(guān)鍵,。許多存在于突觸間的因子以及蛋白酶,、蛋白激酶,、磷酸化酶參與已有蛋白質(zhì)的修飾過程。這些修飾因子通過細胞間的正反饋（對話）依次起作用,，而它們又是受神經(jīng)突觸傳遞的興奮性（如谷氨酸鹽）或抑制性神經(jīng)遞質(zhì)（如伽馬氨基丁酸）調(diào)控,。這種自主正反饋系統(tǒng)還有種內(nèi)建機制用來避免反饋失控，使記憶如核爆炸般地增加,。
盡管羅特勃格的觀點被認(rèn)為離經(jīng)叛道,，他仍認(rèn)為科學(xué)家應(yīng)該不被傳統(tǒng)觀點束縛，提出合理的假說,。對記憶原理的更精確描述有助于診斷和治療精神發(fā)育遲滯,、阿爾茨海默癥等可引起記憶損害的疾病。他說：“可以肯定,，在長期記憶機制研究的各種假說中,，蛋白質(zhì)合成后修飾/正反饋模型有足夠的論據(jù)支持。新假說將開辟大腦長期記憶機制研究的新方向,。”（http://www.bioon.com/）
New theory chalenges current view of how brain stores long-term memory
How do you remember your own name? Is it possible ever to forget it? The memory trace, or engram, "feels" like it is stored permanently in the brain and it will never be forgotten.
Indeed, the current view of memory is that, at the molecular level, new proteins are manufactured, in a process known as translation, and it is these newly synthesized proteins that subsequently stabilize the changes underlying the memory. Thus, every new memory results in a permanent representation in the brain.
But Northwestern University neuroscientist Aryeh Routtenberg has presented a provocative new theory that takes issue with that view. Routtenberg, with doctoral student Jerome L. Rekart, outlined the new theory on memory storage in the January issue of the journal Trends in Neuroscience.
Rather than permanent storage, there is a "dynamic, meta-stable" process, the authors said. Our subjective experience of permanence is a result of the re-duplication of memories across many different brain networks.
For example, one's name is represented in innumerable neural circuits; thus, it is extremely difficult to forget. But each individual component is malleable and transient, and as no particular neural network lasts a lifetime, it is theoretically possible to forget one's own name.
This is seen in the most advanced stages of Alzheimer's disease, the researchers stated.
The advantage of such a precarious storage mechanism is that it is a highly flexible system, enabling rapid retrieval even of infrequent elements, with great advantages over models of permanent storage, said Routtenberg, professor in the department of psychology and in the department of neurobiology and physiology, Judd A. and Marjorie Weinberg College of Arts and Sciences and a leading researcher in the Institute for Neuroscience, Northwestern University.
To achieve this high degree of flexibility, Routtenberg's new theory goes on to propose that the brain stores long-term memory by rapidly changing the shape of proteins already present at those synapses activated by learning.
While it is universally agreed that brain proteins are critical for memory storage, Routtenberg's hypothesis challenges the widely accepted, 40-year-old model that long-term memories are stabilized only once newly synthesized proteins are transported to recently activated synapses.
Indeed, this view is central to the theory of Eric Kandel, who in his Nobel Prize address reinforced the central position of this model in forming long-term memory.
So does memory form because you make more protein, as most neuroscientists believe, or because you change the shape of existing proteins, which are known to be strategically located to effect change within milliseconds of activation?
Part of the answer to this question lies in the fact that there are critical weaknesses in the prevailing view.
"There are enough instances of memory storage in the virtual absence of protein synthesis to compel consideration of alternative models," said Routtenberg.
The authors noted that most of the evidence supporting the current view was obtained by studying the effects of certain drugs, called protein synthesis inhibitors, on memory, leading to the conclusion that synthesis was necessary. The authors outline specific evidence that calls those results into question.
For example, synthesis inhibitors that block the production of new proteins by more than 90 percent often cause no discernible memory impairments. Additionally, protein synthesis inhibitors cause a number of side effects that could lead to memory loss caused by something other than protein synthesis inhibition.
Routtenberg agrees with the view that it is the synapse that is modified in response to learning-associated activity, a position first articulated by Nobelist Ramon y Cajal a century ago. But the difference with the current theory is that he and Rekart do not believe that synaptic modification is brought about by recently synthesized proteins.
Routtenberg's theory, derived from a consideration of extensive, fundamental biochemical information, advocates that learning leads to a post-synthesis (or, post-translational) synaptic protein modification that results in changes to the shape, activity and/or location of existing synaptic proteins. In the Routtenberg-Rekart proposal, this is the only mechanism required for long-term memory.
To maintain some residue of this modification, Routtenberg proposes that the "spontaneous activity" of the brain actually acts to "cryptically rehearse" past events. So, long-term memory storage relies on a positive-feedback rehearsal system that continually updates or fine-tunes post-translational modification of previously modified synaptic proteins. It is in this manner that this model allows for the continual modifications of memories.
In the Routtenberg-Rekart model, post-translational modifications within cells and synaptic dialog and endogenous activity between cells and networks work in concert to perpetuate and update memory representations.
A group of post-translational protein modifications that affect neuronal plasticity – present in activated pre-synaptic and post-synaptic elements and regulated by proteases, kinases and phosphatases – regulate the efficacy of the synapse in response to a learning event.
These modifications are, in turn, maintained via positive feedback between cells (dialog), which are regulated by synaptic excitation (e.g., via the neurotransmitter glutamate) or inhibition (e.g., via the neurotransmitter GABA).
Thus, the self-sustaining positive feedback system also carries built-in control mechanisms that would prevent runaway feedback leading to the detonation of one massive memory or "thermonuclear" engram.
Although Routtenberg's model may represent a radical departure from the current view of how long-term memories are stored, he believes that scientists need to articulate alternative models other than the prevailing one.
A more accurate description will help address issues of memory loss in mental retardation, aging and Alzheimer's disease. Indeed, new hypotheses can lead to the development of new chemical agents that would successfully target the chemical reactions necessary "We would assert that there is enough substance both in the concerns raised and in the post-translational modification/positive feedback model proposed to energize the search for yet more plausible models of long-term memory storage, and to redirect and reinvigorate the quest to understand the brain substrates of information storage," Routtenberg said.
Source: Northwestern University （http://www.bioon.com/）
