早在20世紀(jì)40年代，神經(jīng)學(xué)家懷爾德·潘菲爾德就發(fā)現(xiàn),，病患者能夠在大腦不同區(qū)域受到電擊刺激時,，回憶起餅干氣味等看似隨意的信息。近期進(jìn)行的兩項(xiàng)研究已找到了支持這一記憶儲存理論的證據(jù),，相關(guān)研究報(bào)告發(fā)表在最新出版的Science雜志和Nature雜志網(wǎng)絡(luò)版上,。其中一項(xiàng)基于轉(zhuǎn)基因小鼠的研究，甚至能證明或可操控大腦細(xì)胞,，以產(chǎn)生錯誤的記憶,。
加州斯克利普斯研究院的Mark Mayford及其同事對小鼠進(jìn)行了轉(zhuǎn)基因處理，使它們的神經(jīng)元能夠在大腦注入hM3Dq DREADD受體時,，被再次觸發(fā),。這種受體可由專門的藥物所激活。
研究團(tuán)隊(duì)將小鼠單獨(dú)放在盒子中,，每個盒子接觸到的顏色和氣味都不同,，這將刺激神經(jīng)元形成有關(guān)上述條件的記憶。由于神經(jīng)元會在記憶形成時激發(fā),，同時能在藥物注入時被重新激活,，這使研究人員能夠無意識地誘導(dǎo)小鼠產(chǎn)生和盒子有關(guān)的記憶,。隨后，他們將每只老鼠放入具有不同顏色和氣味的第二個盒子之中,，并為其注入藥物,，使老鼠記住第一個盒子，隨后對其施加輕微的電擊,。
通常來說,，電擊會促使小鼠畏懼其所在的直接環(huán)境，即第二個盒子,。但在這個實(shí)驗(yàn)中,，雖然小鼠受到電擊時正處于第二個盒子之中，但卻保有了關(guān)于第一個盒子的強(qiáng)烈記憶,，小鼠因此對兩個盒子都產(chǎn)生了畏懼感,，即對于直接環(huán)境和虛構(gòu)環(huán)境的雙重恐懼。之前只有在受到注入藥物的刺激時,，身處第二個盒子的小鼠才會對第一個盒子也產(chǎn)生恐慌,。
Mayford認(rèn)為，這種混合的錯誤記憶意味著兩種不同組群的神經(jīng)元可同時編碼一種記憶,，且不會發(fā)生互相干擾,。事實(shí)上，我們可以將新的信息引入記憶,，開辟研究的新世界,。
此外，麻省理工學(xué)院的Susumu Tonegawa及其同事也提出了可產(chǎn)生錯誤回憶和感覺的不同方式,。經(jīng)過感光基因處理的小鼠,，可在生成有關(guān)盒子的記憶時，借助所涉及的神經(jīng)元對光線作出響應(yīng),。當(dāng)小鼠形成關(guān)于盒子的記憶時,，研究團(tuán)隊(duì)對其施加了電擊。隨后其將小鼠放入不同的盒子,，并通過植入小鼠大腦的光纖傳輸光脈沖,。這種對于神經(jīng)元的激活與記憶相關(guān)，與受到打擊而恐懼發(fā)抖的小鼠所處何方并無關(guān)聯(lián),。
當(dāng)研究人員觀察被激活的神經(jīng)元時,，他們發(fā)現(xiàn)，在海馬體的特定區(qū)域內(nèi)大約有2%的細(xì)胞牽涉其中,。Susumu Tonegawa 表示,，這種方法可基于小鼠的經(jīng)歷和習(xí)慣,，誘發(fā)其做出不同類型的復(fù)雜行為,。下一步,，研究團(tuán)隊(duì)將觀測小鼠大腦記憶中心之外區(qū)域?qū)τ诳謶只貞浀捻憫?yīng)，這也是用于證明記憶被存儲于大腦內(nèi)多個獨(dú)立區(qū)域的“終極實(shí)驗(yàn)”,。（生物谷 bioon.com）
doi:10.1126/science.1214985
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Generation of a Synthetic Memory Trace
Aleena R. Garner, David C. Rowland, Sang Youl Hwang, Karsten Baumgaertel, Bryan L. Roth, Cliff Kentros, Mark Mayford
We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos–based transgenic approach to introduce the hM3Dq DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM3Dq-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning.
doi:10.1038/nature11028
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Optogenetic stimulation of a hippocampal engram activates fear memory recall
Xu Liu, Steve Ramirez, Petti T. Pang, Corey B. Puryear, Arvind Govindarajan, Karl Deisseroth,，Susumu Tonegawa
A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.
