一個(gè)由美國紐約大學(xué)和加利福尼亞大學(xué)歐文分校神經(jīng)學(xué)家組成的研究小組利用加利福尼亞海兔,，對(duì)形成短期,、中期和長期記憶過程中,，神經(jīng)元分子活動(dòng)的時(shí)間順序和空間位置進(jìn)行了區(qū)分,。這一成果為記憶形成的分子活動(dòng)提供了最新解釋,，也為開發(fā)相關(guān)疾病的干預(yù)療法帶來了更好的地圖,。相關(guān)論文發(fā)表在最近的美國《國家科學(xué)院學(xué)報(bào)》上,。
“記憶形成不是簡單地將分子活動(dòng)打開或關(guān)閉，而是由分子間相互作用和運(yùn)動(dòng)的復(fù)雜的時(shí)空關(guān)系所產(chǎn)生,。”該研究領(lǐng)導(dǎo)紐約大學(xué)文理學(xué)院院長,、神經(jīng)科學(xué)中心教授托馬斯·卡魯說，“我們的發(fā)現(xiàn)為‘記憶是怎樣產(chǎn)生的’這一問題提供了更深入理解,。”
此前,，神經(jīng)科學(xué)家已經(jīng)從多個(gè)方面揭示了與記憶形成有關(guān)的分子信號(hào)，但對(duì)記憶形成過程中分子的空間關(guān)系,、分子活動(dòng)的時(shí)間順序還知之甚少,。在早些的研究中，已經(jīng)發(fā)現(xiàn)有兩種分子MAPK和PKA與多種記憶形式以及突觸形狀改變有關(guān),，也就是說與神經(jīng)元相互作用后腦中發(fā)生的改變有關(guān),，但還不清楚它們是在何時(shí)、何處以及怎樣發(fā)生這些作用的,。
為解決這一問題,，該研究小組利用了加利福尼亞海兔(一種海洋軟體動(dòng)物，也叫海蛞蝓)的神經(jīng)元,。海兔是一種良好的神經(jīng)生物模型,，它們的神經(jīng)元比高等生物,，如脊椎動(dòng)物，要大10倍到50倍,，而且其神經(jīng)網(wǎng)絡(luò)相對(duì)較小——這些特性讓科學(xué)家很容易檢查記憶形成過程中的分子信號(hào),。此外，它們的記憶編碼機(jī)制在進(jìn)化過程中高度保守,，幾乎沒什么改變,，也和哺乳動(dòng)物的記憶編碼機(jī)制很相似，這些都使它們成為研究人類記憶過程的最佳模型,。
新研究集中在MAPK和PKA這兩種分子上,。研究人員對(duì)海兔進(jìn)行了感受增強(qiáng)訓(xùn)練，對(duì)它們的尾部施加溫和電擊,，誘導(dǎo)它們形成更強(qiáng)的條件反射行為,，即溫和地激活其尾部神經(jīng)結(jié)構(gòu)，然后對(duì)MAPK和PKA的分子活性進(jìn)行檢查,。
他們發(fā)現(xiàn),，MAPK和PKA的活動(dòng)在空間和時(shí)間上協(xié)調(diào)配合，尤其在形成中期記憶(幾個(gè)小時(shí))和長期記憶(幾天)時(shí),，MAPK和PKA的活性都被激發(fā),，MAPK刺激了PKA的活動(dòng)；而在短期記憶(不到30分鐘)中,，只有PKA的活性被激發(fā),，MAPK并未參與。（生物谷Bioon.com）
doi: 10.1073/pnas.1209956109
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Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia
Ye X, Marina A, Carew TJ.
It is widely appreciated that memory processing engages a wide range of molecular signaling cascades in neurons, but how these cascades are temporally and spatially integrated is not well understood. To explore this important question, we used Aplysia californica as a model system. We simultaneously examined the timing and subcellular location of two signaling molecules, MAPK (ERK1/2) and protein kinase A (PKA), both of which are critical for the formation of enduring memory for sensitization. We also explored their interaction during the formation of enduring synaptic facilitation, a cellular correlate of memory, at tail sensory-to-motor neuron synapses. We find that repeated tail nerve shock (TNS, an analog of sensitizing training) immediately and persistently activates MAPK in both sensory neuron somata and synaptic neuropil. In contrast, we observe immediate PKA activation only in the synaptic neuropil. It is followed by PKA activation in both compartments 1 h after TNS. Interestingly, blocking MAPK activation during, but not after, TNS impairs PKA activation in synaptic neuropil without affecting the delayed PKA activation in sensory neuron somata. Finally, by applying inhibitors restricted to the synaptic compartment, we show that synaptic MAPK activation during TNS is required for the induction of intermediate-term synaptic facilitation, which leads to the persistent synaptic PKA activation required to maintain this facilitation. Collectively, our results elucidate how MAPK and PKA signaling cascades are spatiotemporally integrated in a single neuron to support synaptic plasticity underlying memory formation.
