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ERK參與味覺嫌惡制約中不同的「消除」機制
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| 作者 |
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林佩儀 |
| 學校系所 |
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臺灣大學生理學研究所 |
| 地點 |
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全臺 全部
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| 研究內容 |
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[中文摘要]
味覺嫌惡制約（conditioned taste aversion）是一種將不熟悉的味道（制約刺激，CS）結合腹部的不適（非制約刺激，US）而引發動物對這個味道產生嫌惡反應（制約反應，CR）的連結學習。「消除」（extinction）是當不再強化制約刺激時，所造成制約反應減弱的情況。行為實驗的結果指出「消除」是一種「新的抑制學習」過程，不影響原來的制約學習，因為在接受較弱的制約與非制約刺激的連結或是單獨給予非制約刺激之後，已經被「消除」的制約反應會再度表現出來。近年來關於恐懼制約的研究證實「消除」也可能是一種「忘記已學習」的過程，因為當恐懼制約的「消除」與「習得」（acquisition）之間的間隔時間很短，被「消除」的制約反應就不再表現。本實驗利用味覺嫌惡制約的學習模式驗證上述兩種「消除」的機制以及在分子生物學上相關的變化。所使用的實驗動物是鼠齡八週的Long- Evans 雄鼠，利用 2 %的糖水結合以腹腔注射每公斤體重 4 ml濃度 0.15 M 之鋰鹽（LiCl） 所引起的不適，造成雄鼠對糖水產生嫌惡制約反應。若「消除」訓練在前述制約「習得」訓練後 24 小時進行，動物於制約訓練 7 日後，經歷糖水結合較少量鋰鹽（1 ml/kg）的「節餘」（saving）實驗或只給予注射鋰鹽（4 ml/kg）的「重建」（reinstatement）實驗，都會使已「消除」的制約反應恢復。反之，如果「消除」訓練是在制約「習得」訓練後 5 小時進行，則制約反應在上述兩種清況下都無法再度被表現出來。為了釐清造成這兩類行為差異的分子機制，我們利用西方點墨法分析第一次「消除」訓練後內側前額葉皮質（medial prefrontal cortex）、島葉皮質（insular cortex）、中央杏仁核（central nucleus of amygdala）與基側杏仁核（basolateral nucleus of amygdala）等腦區中 extracellular signal-regulated kinase（ERK）的活性，因為 ERK 是在記憶形成過程中不可或缺的蛋白酶。結果顯示，始於制約「習得」訓練後 24 小時的「消除」訓練會改變基側杏仁核中 ERK的活性。然而，若「消除」訓練是在制約「習得」訓練後 5 小時即開始進行，則內側前額葉皮質 ERK的活性會被改變。總而言之，本實驗結果顯示在味覺嫌惡物制約學習中，因為「消除」訓練與「習得」的間隔時間不同，「消除」可能包含「忘記已學習」或「新的抑制學習」的機制，而且這兩種機制分別與內側前額葉皮質及基側杏仁核的 ERK 活性改變有關。
中文關鍵詞：味覺嫌惡制約、消除機制、胞外訊息調控激酶、內側前額葉皮質、杏仁核
[英文摘要Abstract]
Conditioned taste aversion (CTA) is a type of associative conditioning in which an unfamiliar taste (conditioned stimulus, CS) becomes associated with malaise (unconditioned stimulus, US), resulting in an aversive response (conditioned response, CR) to the taste. Extinction is decline in CR following non-reinforcement of CS. Behavioral evidence indicates that extinction is a new inhibitory learning process by showing that the original conditioning would not be erased as the extinguished CR reappears with presentation of fewer learning trials (saving) or unconditioned stimulus (reinstatement). However, recent studies suggested that extinction of fear conditioning could be an unlearning process that erases the original conditioning as extinguished CR would not reappear if the time interval between fear acquisition and extinction was short. The present study examined these two aforementioned mechanisms of extinction and the related molecular changes in CTA. Male Long-Evans rats (8-week-old) acquired CTA by associating between 0.2% sucrose solution with malaise induced by i.p injection of 0.15 M LiCl 4 ml/kg. When extinction trials were performed at 24 h after the CTA acquisition, rats re-exhibited the extinguished CR following the experience of sucrose paired by lower dose LiCl (1 ml/kg) injection (saving) or the injection of LiCl (4 ml/kg) alone (reinstatement) 7 days after CTA acquisition. In contrast, rats receiving extinction trials 5 h after acquisition could not retrieve from aversive memory in both situations. In order to reveal the molecular mechanisms of extinction contributing to such differences, we used western blot analysis to examine the activation of the extracellular signal-regulated kinase (ERK), which is critically involved in memory formation in the medial prefrontal cortex (mPFC), insular cortex, central nucleus of amygdala, and basolateral nucleus of amygdala (BLA) after the first extinction trial. Our data demonstrate that extinction trial beginning at 24 h after acquisition induced expression of ERK activation in BLA. In contrast, when the first extinction trial was performed at 5 h after acquisition, ERK would be activated in mPFC. Together, these findings suggest that there are both unlearning and new inhibitory learning mechanisms of extinction in CTA depending on the time intervals between acquisition and extinction, and the ERK transduction pathway could be activated separately in mPFC and BLA by these two different mechanisms.
Keywords：conditioned taste aversion、extinction、ERK、medial prefrontal cortex、amygdala
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