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研究生:林蕙竹
研究生(外文):Hui-Chu Lin
論文名稱:應用Adra2c基因剔除/lacZ基因嵌入小鼠探討正腎上腺素Alpha2C亞型受體在邊緣系統中的功能
論文名稱(外文):Functional Implication of Alpha2C Adrenoceptors in Limbic System Using Adra2c Knock-out / lacZ Knock-in Mice
指導教授:錢嘉韻錢嘉韻引用關係
指導教授(外文):Alice Chien Chang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:102
中文關鍵詞:正腎上腺素受體Adra2c基因剔除/lacZ基因嵌入小鼠海馬迴之長期增益效應NMDA受體鈣離子結合蛋白情緒性記憶側邊腦中膈
外文關鍵詞:AdrenoceptorAdra2c-knockout/lacZ knockin micehippocampal long-term potentiationNMDA receptorcalcium binding proteinemotional memorylateral septum
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在中樞神經系統中的正腎上腺素(norepinephrine,NE)由中腦藍斑核投射至整個中樞神經系統,影響相當廣泛;範圍上至大腦皮層、海馬迴和視丘,下至腦幹、小腦與脊髓。當正腎上腺系統失調時,可能會影響認知與情緒的功能而導至許多心理障礙症。正腎上腺素受體(adrenoceptors,ARs)為 G-protein-coupled receptors(GPCRs),其中α2-AR 所偶合的 GDP-binding protein(G protein)為抑制性的 Gi 蛋白,並且可再分為三種亞型 – α2A、α2B、α2C。利用張南驥教授實驗室建立的 Adra2c基因剔除/lacZ基因嵌入小鼠,可以直接觀察到α2C-AR 在中樞神經系統中的表現位置,進而可以針對相關的核區來研究。
由於海馬迴會表現α2C-AR,而海馬迴在學習與記憶的功能上扮演重要的角色,因此本論文針對α2C-AR 在海馬迴中對於學習與情緒記憶上扮演的角色作進一步的分析。之前已觀察到α2C-AR 可能參與情緒記憶,而在海馬迴的長期增益效應(long-term potentiation, LTP)的確也偵測到基因型之間的差異性。經由免疫組織染色以及西方墨點法分析後,發現在α2C-AR 缺失的小鼠:1) 其背側海馬迴中的 NMDA receptor NR1 subunit 蛋白質表現量明顯較野生型小鼠減少;2) 在背側海馬迴中原本會表現α2C-AR 的錐體細胞之 calbindin-D28K 蛋白質表現量也明顯減少。以上的結果有可能是造成 Adra2c 基因剔除小鼠在群居狀況下,其海馬迴 CA3-CA1 突觸間的長期增益效應幅度較野生型小鼠低的現象的原因。
另外在 lateral septum 中 BDNF 的免疫組織染色也觀察到,在 Adra2c 基因剔除小鼠中,投射到 mediolateral zone的 BDNF 蛋白質明顯較野生型少。由於 BDNF 投射在此區域可以調控 GABAergic spiny interneron 細胞的 calbindin-D28K 蛋白質的表現量。在同一個區域中的確也觀察到 calbindin-D28K 的蛋白質表現量有減少的趨勢。由於 septum 對於其他邊緣系統區域之間的連結扮演了中繼站的角色,並且可以調控所傳遞的訊息,因此在 Adra2c 基因剔除小鼠 lateral septum 中的異常,可能會影響其他邊緣系統之間的訊息傳遞而造成行為上的改變。
在暴力行為的實驗中,已經發現 Adra2c 基因剔除小鼠具有較高的暴力傾向。而在行為測試之後 Adra2c 基因剔除小鼠海馬迴中的長期增益效應之增益幅度較群居或是隔離的Adra2c 基因剔除小鼠增高許多,並且明顯高於同樣經過行為測試的野生型小鼠,但是野生型小鼠的長期增益效應並沒有因為長期隔離或行為測試而有明顯的改變。推測可能是由於 Adra2c 基因剔除小鼠的正腎上腺素和血清素及多巴胺系統之間不平衡而造成的影響。由上所述可以發現在正常生理狀況下, NE 經由α2C-AR 可以調控神經細胞的 興奮性(excitability) 而影響長期增益效應,但由於暴力行為之前後腦中多種調控系統之間的平衡可能有所改變,因此在缺失α2C-AR 的情況下會在不同的行為經驗後觀察到海馬迴長期增益效應的異常。
In the central nervous system (CNS), the majority of norepinephrine (NE) neurons are located in the locus coeruleus. The NE axon fibers project to extensive areas of the brain including cerebral cortex, hippocampus, thalamus, brain stem, cerebellum and spinal cord. The NE neurotransmission system has been implicated in cognitive and affective functions and disturbed NE neurotransmission is known to result in psychiatry disorders. α2- adrenoceptors (α2-ARs) are one of the G-protein-coupled receptor (GPCR) classes mediating the effects of NE. They are further classified into 3 subtypes; α2A-, α2B- and α2C-ARs. Using Adra2c-knockout/lacZ- knockin (KO-KI) mice, we can map directly the expression pattern of α2C-AR in the CNS, and also investigate its function in these areas.
One of the major brain regions with significant α2C-AR expression is hippocampus, known to be key to learning and memory. We have previously demonstrated that the Adra2c-KO/lacZ-KI mice have a higher tendency of aggression than the wildtype (WT) control (C57BL/6). The present study was aimed to delineate the functional role of α2C-AR in emotional memory in this area. A modified Residenet-Intruder paradigm (RI) was used as a test of aggression and its associated emotional memory. The hippocampal LTP of KO mice post-RI not only was significantly higher than group housing or isolated KO-KI mice, it may also be higher than that of the WT after the behavioral test. But the LTP of WT mice after behavioral test was not different from its group housing or isolated counterparts. We suggest that a2C-AR is involved in the induction and maintenance of LTP elicited by this particular type of emotional memory. The deficiency of α2C-AR in the CA1 pyramidal neurons of both dorsal and ventral hippocampus might significantly affect the NE transmission and its intricate networking with the serotonin and dopamine systems in the CNS.
Using immunohistochamistry (IHC) and Western blot, we have found in the α2C-AR-deficient mice: (i) the expression level of NR1 in dorsal hippocampus is lower than that of the WT, (ii) the expression level of calbindin-D28K was decreased in dorsal hippocampal CA1 pyramidal cells, where α2C-AR expression is abundant in WT. It is possible that these changes may be the cause of the unsustainable LTP in the α2C-AR deficient mice. Moreover, the decreased level of BDNF found in lateral septum of the α2C-AR deficient mice suggest that the catecholamine (NE and DA) projections into this area may be decreased which led to the decrease of calbindin-D28K in the GABAergic spiny interneurons. Since most messages between different areas of the limbic system are processed through and modulated by septum, so the abnormality in the lateral septum may affect the regulation of neurotransmission between other limbic system areas.
In conclusion, the present studies provide evidence that α2C-AR might take part in the regulation of excitability of hippocampal neurons. Because the balance between different systems in the brain may not be the same before and after behavioral task, while lacking α2C-AR cause the imbalance between different modulatory systems, so the LTP elicited from different behavioral experiences was abnormal under the condition of α2C-AR deficiency.
中文摘要 -----------------------------------------------------------------------------Ⅰ
Abstract --------------------------------------------------------------------------------Ⅱ
壹、 緒論 ---------------------------------------------------------------------------1
貳、 材料及方法 ------------------------------------------------------------------17
一、實驗動物 ……………………………………………………………… 17
二、Genomic DNA的萃取與基因型分析 ………………………17
三、受隔離小鼠之暴力行為測試(Resident-intruder paradigm)……19
四、記錄海馬迴中 CA3 到 CA1 之間 population spike 的長期增益效應 ………………19
五、小鼠灌流、腦組織切片…………………………………………21
六、原位(in situ)X-gal染色…………………………………………21
七、免疫組織染色………………………………………………………22
八、以Western Blot 定量組織中蛋白質總表現量………………24
九、數據分析……………………………………………………………27
參、 實驗結果-----------------------------------------------------------------29
一、Adra2c基因剔除/lacZ基因嵌入小鼠基因型分析 …………29
二、在小鼠海馬迴 CA1 所記錄到的長期增益現象,在群居或
進行暴力行為測試之後的變化…………………………………30
三、暴力行為或長期增益效應相關基因的表現 ……………34
肆、 結果討論與未來展望-----------------------------------------------39
一、在群居狀況下α2C-AR缺失對海馬迴CA1細胞的生理影響 39
二、暴力行為測試後對於海馬迴CA1細胞的生理影響 ………42
三、在Adra2c基因剔除小鼠腦中的 GABAergic system……………45
四、由Septum探討其他系統之間的調控 …………………………47
五、Adra2c基因剔除小鼠與精神分裂症(Schizophrenia)的研究 …………………………48
六、總結 ……………………………………………………………50
伍、 參考文獻 --------------------------------------------------------51
陸、 圖表 --------------------------------------------------------------62
柒、 附錄 ------------------------------------------------------------91
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