你是怎么记住自己名字的？是否有可能忘记它？这种记忆的痕迹似乎永久镌刻在大脑中，不可能忘怀。目前，对于长期记忆的观点是，从分子水平看，产生了新蛋白质，也即蛋白质的翻译过程。是这些新合成的蛋白质保存了记忆。也就是说，每个新记忆都在脑中对应着相应的蛋白质。但美国西北大学神经学家罗特勃格及其博士生杰罗米-里卡特在《神经病学》2005年1月刊上载文提出了新观点，对上述传统观点提出了挑战。
罗特勃格说，除永久记忆外，大脑中还有种“动态的、亚稳定”记忆过程。凭主观经验，人们一直认为永久记忆是记忆通过许多大脑神经网络反复加强的结果。比如，我们自己的名字存在于数不清的神经回路中，很难遗忘。但每个神经回路都具有可塑性，也不可能终生存在，所以从理论上讲人可能忘掉自己的名字。这在严重的阿尔茨海默症患者身上已经得到验证。这种不稳定的记忆机制有很大适应性，即使在少数情况下发生错误也可得到迅速补救，这相比永久记忆，优越性显而易见。
为解释记忆的高度适应性，罗特勃格的新观点认为学习过程激活了某些神经突触，需要储存长期记忆时，大脑迅速改变其中某些蛋白质的构型。这挑战了已被人们接受了40年的传统理论：新合成的蛋白质被运送到最近激活的突触后，保存了长期记忆。事实上，上述传统观点是艾里克-坎德尔理论的核心，他因此曾获得诺贝尔奖金。
那么，记忆究竟是象大多数学者认为的那样，基于蛋白质的合成，还是如新观点所言，是已有蛋白质构型的改变？至少传统观点有严重缺陷，有足够事实证明没有蛋白质合成，一样能保存记忆。罗特勃格指出，传统观点的主要证据来源于对蛋白合成抑制剂的研究，但这些研究结果值得商榷。例如，足以阻断90％蛋白质合成的蛋白合成抑制剂通常不对记忆造成损害，而其非蛋白合成抑制的副作用却可造成记忆丢失。
罗特勃格同意一百年前关于学习激活神经突触的理论。但他不同意目前有关这种激活是基于新合成蛋白质的说法。根据大量基础生物化学过程研究，他认为学习引起突触已有蛋白质的构型修饰，这种构型修饰是保存长期记忆的唯一机理。为进一步解释构型修饰，罗特勃格认为大脑平时实际上不断地“秘密复习”着过去的体验。长期记忆的形成有赖于这种正反馈复习机制，在这种机制下不断更新或微调着已有蛋白质的构型。细胞内的蛋白质合成后修饰、突触间信息传递和神经细胞、神经网络间的和谐互动是维持永久记忆的关键。许多存在于突触间的因子以及蛋白酶、蛋白激酶、磷酸化酶参与已有蛋白质的修饰过程。这些修饰因子通过细胞间的正反馈（对话）依次起作用，而它们又是受神经突触传递的兴奋性（如谷氨酸盐）或抑制性神经递质（如伽马氨基丁酸）调控。这种自主正反馈系统还有种内建机制用来避免反馈失控，使记忆如核爆炸般地增加。
尽管罗特勃格的观点被认为离经叛道，他仍认为科学家应该不被传统观点束缚，提出合理的假说。对记忆原理的更精确描述有助于诊断和治疗精神发育迟滞、阿尔茨海默症等可引起记忆损害的疾病。他说：“可以肯定，在长期记忆机制研究的各种假说中，蛋白质合成后修饰/正反馈模型有足够的论据支持。新假说将开辟大脑长期记忆机制研究的新方向。”
来源：生物谷
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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
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