以斑馬魚模式進行腦功能側化相關研究
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2017
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斑馬魚(Denio rerio)因其胚胎透明、容易飼養及觀察等優點，近年成為神經與發育生物學研究之新興動物模式。斑馬魚的神經系統與大多數硬骨魚類似，其端腦 (telencephalon) 的主要構造、相對體積大小、解剖位置及功能與哺乳類之邊緣系統 (limbic system) 相似，為一個易於操作的端腦功能研究模式。本篇論文即利用斑馬魚的各項研究優勢，進行三個部分的研究，以探討斑馬魚端腦的功能、相關之運作過程與訊息傳遞之機轉。在第一章中，我們延續先前的實驗成果，利用吸引法(aspiration)對端腦進行直接的破壞，以探究端腦在空間記憶形成上所扮演的角色，結果顯示端腦的左、右兩半球，分別對於空間及情緒性記憶 (emotional memory) 有著不同的影響，特別是在獲取 (acquisition) 及重新擷取 (retrieval) 的過程中，而對端腦進行單側破壞(unilateral ablation)，均可干擾情緒性記憶的形成。在第二章中，由於過去文獻發現X染色體脆折症 (fragile X syndrome) 患者在腦側化 (cerebral lateralization) 的表現上受到影響，故藉著fmr1基因剔除品系斑馬魚，探討此斑馬魚身上，是否會呈現類似人類病患之異常情緒性行為，結果證實了fmr1之缺損，會造成斑馬魚情緒性行為之發展異常，也會干擾了抑制性逃避記憶 (inhibitory avoidance memory) 的形成。在第三章中，主要使用了電生理的實驗方式，探究斑馬魚端腦外側 (Dl) 到端腦內側 (Dm) 之訊號傳遞。我們發現不只通往同側的端腦內側 (ipsilateral telencephalic Dm region) 有訊號傳遞，而在對側 (contralateral) 端腦之內側亦有類似的訊號傳遞，並且兩側同時存在着代表神經可塑性的長期增强效應long-term potentiation (LTP) 及長期抑制效應long-term depression (LTD) 現象，兩者的作用機制需要麩胺酸NMDA及代謝性受體 (metabotropic glutamate receptor) 的參與；其神經可塑性之LTP與LTD模式，在左、右側端腦中的表現並非完全相同，這呼應了第一階段的實驗結果，進一步證實了斑馬魚的左右側端腦，在處理學習與記憶的功能時，扮演著不同的角色。最後我們也發現，有別於哺乳類動物，斑馬魚主要藉由前連合 (anterior commissure) 構造進行兩側端腦的訊息傳遞。
總結上述三階段的研究成果，可證明斑馬魚端腦中亦存在著腦側化的現象，而斑馬魚確實能應用於探討腦側化的機轉研究。
Zebrafish is an important animal model for the neuroscience and developmental biology researches, the transparent egg and embryo of zebrafish which is convenience to observe the developmental process. It shares similar neural structure and function among teleost. The simplicity of its neural system is more convenient for studying limbic system function than conventional mammalian models. The present study used these advantages to achieve two research goals. In chapter one, we observed the abnormality of emotional behavior in fmr1 KO zebrafish. In chapter two, we used electrophysiological recording paradigms to study the ipsilateral and contralateral synapse between lateral diencephalon (Dl) and medial diencephalon (Dm). Our results showed consistency with the previous study showing the neural projection between Dl-Dm. We also proved that the projection does not only link to ipsilateral but also connected with the contralateral telencephalon. Most interestingly, both LTP and LTD were form in contralateral Dl and different mechanisms underlie the synaptic plasticity between ipsilateral and contralateral side of TEL. Results of behavioral experiments showed each side of telencephalon may play different role in learning and memory. Furthermore our results also suggested the possibility that the uneven distribution of metabotropic glutamate receptor type one (mGluR1) on telencephalon may essential for the cerebral lateralization in zebrafish.
Zebrafish is an important animal model for the neuroscience and developmental biology researches, the transparent egg and embryo of zebrafish which is convenience to observe the developmental process. It shares similar neural structure and function among teleost. The simplicity of its neural system is more convenient for studying limbic system function than conventional mammalian models. The present study used these advantages to achieve two research goals. In chapter one, we observed the abnormality of emotional behavior in fmr1 KO zebrafish. In chapter two, we used electrophysiological recording paradigms to study the ipsilateral and contralateral synapse between lateral diencephalon (Dl) and medial diencephalon (Dm). Our results showed consistency with the previous study showing the neural projection between Dl-Dm. We also proved that the projection does not only link to ipsilateral but also connected with the contralateral telencephalon. Most interestingly, both LTP and LTD were form in contralateral Dl and different mechanisms underlie the synaptic plasticity between ipsilateral and contralateral side of TEL. Results of behavioral experiments showed each side of telencephalon may play different role in learning and memory. Furthermore our results also suggested the possibility that the uneven distribution of metabotropic glutamate receptor type one (mGluR1) on telencephalon may essential for the cerebral lateralization in zebrafish.
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斑馬魚, 端腦, 腦側化, fmr1基因, 長期增益作用, 長期抑制作用, zebrafish, telencephalon, brain lateralization, fmr1 gene, LTP, LTD