執行前額葉皮質工作記憶時Arc蛋白的表現

The Expression of Activity-regulated Cytoskeleton-associated Protein during Prefrontal Working Memory

劉佩君(Pei-Chun Liu)

指導教授 ： 陳贊如

高雄醫學大學/醫學院/生理及分子醫學研究所/碩士(2011年)

https://doi.org/10.6832/KMU.2011.00116

摘要

哺乳動物的大腦前額葉皮層 (prefrontal cortex) 是腦內最高等的聯合區。諸如注意力、計畫能力、以及決策能力等認知功能，端賴大腦前額葉皮層透過工作記憶 (working memory) 的程序方能順利執行。工作記憶是一種將現有資料做短暫地儲存與處理的能力，待工作事項完成後，此短暫儲存的資料會遭抹除，以避免對下一個工作事項造成干擾。雖然一般認為大腦前額葉皮層的工作記憶與神經網絡長期記憶的歷程無關，然而諸多證據卻指出，透過行為訓練能夠提昇工作記憶的表現。此提昇過程伴隨著大腦前額葉皮層多巴胺 D1 接受器 (dopamine D1 receptors) 的活性增加，顯示突觸可塑性 (synaptic plasticity) 在大腦前額葉皮層的功能扮演某種角色，然而目前科學界對此細胞機制的了解有限。最近的研究指出，一種早期基因的產物 Arc蛋白 (全名為 Activity-regulated cytoskeleton- associated protein) 在突觸可塑性過程中扮演關鍵作用的角色。基於此原因，本研究嘗試以 Arc 蛋白的表現偵測大腦前額葉皮層進行工作記憶的突觸可塑性歷程，並試圖探討多巴胺 D1 接受器於此歷程的調節角色。本研究使用 T 型迷宮，訓練大白鼠執行延宕性非樣本配對任務 (delayed non-match to sample task)，藉此建立大白鼠執行工作記憶的測試。研究結果顯示，大白鼠執行延宕性非樣本配對任務測試後，於大腦內側前額葉皮層 (medial prefrontal cortex) 可發現 Arc 蛋白的表現明顯增加。於此區域內注射多巴胺 D1 接受器的拮抗劑 (SCH23390)，會造成工作記憶的表現明顯變差，而且此區域內的 Arc 蛋白表現量明顯減少，顯示多巴胺 D1 接受器具有調節 Arc 蛋白表現的能力。此外，在施予 Arc 反序寡核苷酸 (Arc antisense oligodeoxynucleotides) 之後，大白鼠執行工作記憶的能力受到顯著破壞，顯示 Arc 蛋白的表現為大腦前額葉皮層執行工作記憶所不可或缺的成份。綜合目前結果，大腦前額葉皮層執行工作記憶時，多巴胺 D1 接受器能夠調節 Arc 蛋白的表現，並藉由 Arc 蛋白進行突觸可塑性的歷程。

關鍵字

工作記憶 ； 多巴胺 ； 前額葉皮質 ； 突觸可塑性

並列摘要

The mammalian prefrontal cortex (PFC) is the highest association area and is essential for cognitive functions, such as attention, planning, and decision-making, all these functions are executed by working memory. Working memory is the capacity to storage information in mind temporarily. Once the information is used, it will be forgotten to minimize conflicts with subsequent decisions. Although prefrontal cognitive functions have been thought to be independent of long-lasting neuronal modifications of the network, the evidence showed that training-related improvements in working memory is associated with an increase in brain activity and with changes in prefrontal dopamine D1 receptor (D1R) binding potential. This dopamine D1 receptor-associated plasticity demonstrates the reciprocal interplay between behavior and cellular biochemistry, whereas the biochemical markers underlying such prefrontal synaptic plasticity are still unknown. Recently, an immediate early gene product, activity-regulated cytoskeleton-associated protein (Arc), has been confirmed to play an essential role in synaptic plasticity. Based on the observation of Arc as a key regulator in synaptic plasticity, an attempt is made in the present study to examine whether the expression of Arc protein is modulated by D1R activation and involved in prefrontal working memory. In order to evaluate the working memory in animal, rats were trained to perform the delayed non-match to sample task in a T-maze. The results showed that Arc expression in the medial prefrontal cortex (mPFC) was significantly increased after performing the delayed non-match to sample task. Following the administration of D1R antagonist (SCH23390) into the mPFC, rat’s working memory was impaired and the Arc expression was decreased, indicating that working memory-mediated Arc expression may be regulated by D1R. Furthermore, after infusion of Arc antisense oligodeoxynucleotides into the mPFC, the performance of working memory was seriously impaired, indicating that Arc protein may be necessary for the performance of working memory. In summary, these results indicate that D1R plays an essential role in regulating the expression of Arc protein during the execution of prefrontal working memory.

並列關鍵字

working memory ； dopamine ； prefrontal cortex ； synaptic plasticity ； activity-regulated cytoskeleton-associated protein (Arc)

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