特殊的脑细胞可形成长期记忆的生化机制 [美国媒体]

Biochemical Mechanism Could Explain How Long-Term Memories Are Formed

形成长期记忆的生化机制

During the holidays, we often remember the past and create new memories. But, why do some memories fade away while others last forever? Scientists at the Stowers Institute for Medical Research have identified a possible biochemical mechanism by which the specialized brain cells known as neurons create and maintain a long-term memory from a fleeting experience.

在合家欢庆的节日里，我们忆苦思甜，制造新的记忆。不过您有没有想过，为何有些记忆会渐渐模糊直至消失，而另一些则会刻骨铭心？Stowers医学研究所的科学家们发现了特殊的脑细胞——神经元将转瞬而逝的生活片段记录在脑中并贮存为长期记忆的一种可能的生物化学机制。

The research, conducted by Stowers Associate Investigator Kausik Si, Ph.D., and his team, is published in the current issue of the journal Cell. Their research builds upon previous studies by Si and Eric Kandel, M.D., of Columbia University and other scientists. These studies revealed that both short-term and long-term memories are created in synapses, the tiny junctions between neurons. A transient experience – one source of our memories – is capable of producing an enduring change in the strength of the synaptic connection, says Si.

该研究是由副研究员Kausik Si博士及其科研队伍进行的，最发表在了最近一期《Cell》杂志上。他们的研究建立在Si博士和哥伦比亚大学Eric Kandel医学博士以前的一个研究成果之上。这些研究揭示了短期记忆和长期记忆都是由微小的神经元连接器——突触创造的。Si博士介绍说，短暂的生活经历是我们记忆的来源之一，可以使神经突触的连接强度产生持久的变化。

For a memory to endure, and not fade away, the synaptic connections must be kept strong. In a previous study, Si and Eric Kandel, M.D identified CPEB as a synaptic protein that is responsible for maintaining the strength of these connections in the sea slug, a model organism used in memory research. In subsequent research at the Stowers Institute, Si and his team identified Orb2 as the fruit fly version of the CPEB synaptic protein.

要想让一个记忆持久而不消退，就需要突触连接保持强度。Si和Eric Kandel之前的研究发现，一种突触蛋白CPEB可以保持海参——一种被用来进行记忆研究的模型生物——体内神经突触连接的强度。而在Stowers研究所随后进行的研究中，Si及其科研团队发现Orb2就是果蝇体内的CPEB突触蛋白。



Unstimulated Synapse vs. Stimulated Synapse Credit: Kausik Si Lab.

未受刺激的突触和后刺激后的突触。来源：Kausik Si实验室

In their latest study, Mohammed ‘Repon’ Khan, a predoctoral researcher in the Si Lab and first author of the Cell paper, determined that Orb2 exists in two distinct physical states, monomeric and oligomeric. Monomeric Orb2 is a single molecule capable of binding to other molecules. Like CPEB, oligomeric Orb2 is prion-like – that is, it’s a self-copying cluster. However, unlike disease-causing prions, oligomeric Orb2 and CPEB are not toxic.

在他们最新的研究中，Si实验室的博士后研究员，同时也是这篇发表在《Cell》上的论文的第一作者Mohammed ‘Repon’ Khan，确认了Orb2存在两种物理状态：单体和寡聚体。单体的Orb2是一种可与其他分子相连接的单分子。而寡聚体的Orb2就像CPEB一样是一种朊病毒类似物——意即它可以进行自我复制。但是与可致病的朊病毒不同，寡聚体的Orb2和CPEB是没有毒性的。

The paper describes how monomeric Orb2 represses while oligomeric or prion-like Orb2 activates a crucial step in the complex cellular process that leads to protein synthesis. During this crucial step, messenger RNA (mRNA), which is a RNA copy of a gene’s recipe for a protein, is translated by the cell’s ribosome into the sequence of amino acids that will make up a newly synthesized protein.

这篇论文描述了单体Orb2是如何在寡聚体Orb2活跃时抑制自己的。在合成蛋白质的复杂细胞程序中，至关重要的一步需要寡聚体Orb2的活跃。在这至关重要的一步中，信使RNA（mRNA）被细胞的核糖体翻译为一系列氨基酸，这些氨基酸将会合成新的蛋白质。mRNA是基因为合成蛋白而产生的一种RNA拷贝。

“We propose that the monomeric form of Orb2 binds to the target mRNA, and the bound mRNA is kept in a repressed state,” explains Khan.
The Stowers scientists also determined that prion-like Orb2 not only activates translation but imparts its translational state to nearby monomer forms of Orb2. As a result, monomeric Orb2 is transformed into prion-like Orb2, and its role in translation switches from repression to activation. Si thinks this switch is the possible mechanism by which fleeting experiences create an enduring memory.

“我们计划将单体形式的Orb2连接到目标mRNA上，并且将被连接的mRNA保持在抑制状态，”Khan解释说。Stowers的科学家们还确认了朊病毒类似体的Orb2不仅在翻译时活跃，并且会将自己的这种翻译状态透露给附近的单体Orb2。于是，单体Orb2就会转变为朊病毒类似体的Orb2，这在翻译中起到了从抑制状态变为活跃状态的开关作用。Si认为这种转变可能就是将短暂的生活经历变成持久记忆的机制。

“Because of the self-sustaining nature of the prion-like state, this creates a local and self-sustaining translation activation of Orb2-target mRNA, which maintains the changed state of synaptic activity over time,” says Si.

“正是这种可自我维持的朊病毒类似体的状态，创造了一种局部可自我维持的Orb2-目标mRNA翻译活跃物，从而保持了突触状态长时间的改变，”Si说道。

The discovery that the two distinct states of Orb2 have opposing roles in the translation process provides “for the first time a biochemical mechanism of synapse-specific persistent translation and long-lasting memory,” he states.

研究发现了Orb2这两种截然不同状态，在翻译中担任的角色也完全相反，“这是第一次发现突触在维持翻译和长久的记忆中的特殊生化机制，”他如此声明。

“To our knowledge, this is the first example of a prion-based protein switch that turns a repressor into an activator,” Si adds. “The recruitment of distinct protein complexes at the non-prion and prion-like forms to create altered activity states indicates the prion-like behavior is in essence a protein conformation-based switch. Through this switch, a protein can lose or gain a function that can be maintained over time in the absence of the original stimuli. Although such a possibility has been anticipated prior to this study, there was no direct evidence.”

“就我们所知，这是第一例朊病毒型蛋白质开关，可以使一种抑制体变为活跃体，”Si补充说。“这种特殊蛋白复合体的募集——包括非朊病毒类似体和朊病毒类似体两种形态——改变了突触的状态，指示了这种朊病毒类似体的行为本质上是一种蛋白构造开关。通过这种开关，蛋白质可以失去或者获得一种功能，并且在失去原始刺激后仍能长时间维持。虽然这种可能性在研究开始之前就已经预料到了，但是那时并没有直接的证据。”