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研究生:陳俞仰
研究生(外文):YU-YANG CHEN
論文名稱:N-甲基天門冬胺酸鹽受器調控雄鼠視前區性別差異性神經核神經原存活之角色探討
論文名稱(外文):The role of NMDA receptor in mediatingneuronal survival in the SDN-POA of male rats during development
指導教授:許勤許勤引用關係
指導教授(外文):CHIN HSU
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
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:2001
畢業學年度:90
語文別:中文
論文頁數:86
中文關鍵詞:N-甲基天門冬胺酸鹽受器視前區性別差異性神經核凋亡睪固酮
外文關鍵詞:NMDA receptorSDN-POAapoptosistestosterone
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雄鼠視前區性別差異性神經核(SDN-POA)之核體積比雌鼠大約五到七倍,由於雄鼠在胚胎第十七到第十九天具有睪固酮高峰,此高峰保護了SDN-POA核區免於出生第七到第十天細胞凋亡。睪固酮高峰經由轉變成雌二醇後對於保護SDN-POA核區發育過程中免於細胞凋亡扮演重要角色,然而睪固酮高峰對於保護SDN-POA核區免於細胞凋亡的分子機轉仍未知。我們先前的研究結果亦顯示,雄鼠視前區在出生第一及第三天NMDA受器次單位NR1蛋白質的表現顯著多於雌鼠,根據先前報告指出雌二醇可增加海馬迴的NMDA受器數目,而利用MK-801阻斷NMDA受器的活性則會增加腦部神經細胞(如海馬迴CA1區、視丘、下視丘、皮質等)在發育過程中的細胞凋亡,但NMDA受器活性是否受睪固酮高峰影響並未有直接證據。我們猜測NMDA受器可能是睪固酮保護SDN-POA核區神經細胞免於凋亡的仲介調節者。
為了瞭解胚胎時期睪固酮的高峰對於SDN-POA組織型態改變以及對於NMDA受器表現之影響,我們將懷孕母鼠注射睪固酮或予以固定不動壓力來模擬或消除睪固酮高峰,並取其出生幼鼠做實驗。實驗動物分成四組:(1) 對照雄鼠 (2) 模擬睪固酮高峰(androgen sterilized rat; ASR)之雌鼠 (3) 消除睪固酮高峰(prenatal stressed; PNS) 之雄鼠 (4) 對照雌鼠。胎鼠於胚胎第18天犧牲並以RIA測定血中睪固酮之濃度。也測量出生後第八天SDN-POA的神經細胞密度,核區總體積,神經細胞總數,皺縮之比例,並利用TUNEL染色來評估神經細胞凋亡比例。部分胎鼠於出生第一天犧牲,NR1及NR2D (分別為NMDA受器之次單位)之蛋白質與mRNA的表現利用西方墨點法及RT-PCR之方式分別測定,來觀察睪固酮的暴露是否影響NMDA受器之表現。結果顯示:(1) 可成功的看到胚胎第18天睪固酮的濃度在對照雄胎鼠顯著高於對照組雌胎鼠, PNS雄胎鼠顯著低於對照雄胎鼠,ASR雌胎鼠則顯著高於對照雌鼠。(2) 對照雄鼠SDN-POA之NR1蛋白質濃度顯著高於對照雌鼠。在ASR雌鼠及PNS雄鼠之NR1蛋白質表現則分別類似於對照雄鼠及對照雌鼠。但是NR1 mRNA的表現在四組當中沒有顯著差異。(3) 對照雄鼠NR2D 蛋白質及mRNA之表現顯著高於對照雌鼠。而ASR雌鼠與對照雄鼠其蛋白質及mRNA之表現是相似的, PNS雄鼠及對照雌鼠其蛋白質及mRNA之表現量相近。(4) 神經密度在SDN-POA中四組皆無顯著差異,神經核體積及神經細胞總數對照雄鼠高於對照雌鼠,而神經核體積及神經細胞總數ASR雌鼠與對照雄鼠之間或PNS雄鼠與對照雌鼠之間則無顯著差異。神經皺縮之比例對照雄鼠顯著低於對照雌鼠,而神經皺縮的比例ASR雌鼠與對照雄鼠之間或PNS雄鼠與對照雌鼠之間則無顯著差異。 (5) 細胞凋亡比例對照雌鼠顯著高於對照雄鼠,而ASR雌鼠細胞凋亡比例則類似於對照雄鼠,PNS雄鼠細胞凋亡比例則類似於對照雌鼠。由此可知睪固酮的高峰可增加NMDA受器的表現並影響雌雄鼠SDN-POA的型態變化與凋亡。為了進一步確定NMDA受器對於雄鼠發育過程中SDN-POA的神經細胞凋亡所扮演的角色,我們使用MK-801 (非競爭型NMDA受器通道阻斷劑)阻斷NMDA受器後觀察細胞凋亡之情形,實驗動物分成四組,分別為 (1) 對照雄鼠 (2) MK-801 處理之雄鼠 (3) 對照雌鼠 (4) MK-801 處理之雌鼠。於出生第八天用TUNEL染色來評估SDN-POA細胞凋亡比例。實驗結果顯示對照雄鼠SDN-POA細胞凋亡比例顯著低於對照雌鼠,以MK-801阻斷NMDA受器後,雄鼠SDN-POA細胞凋亡比例顯著增加。但雌鼠及經MK-801處理其細胞凋亡比例則無顯著改變。
以上結果顯示,性別分化過程中出生前睪固酮的暴露可能藉由增加NMDA受器之表現,來預防SDN-POA神經細胞免於細胞凋亡。

The sexual dimorphic nucleus of preoptic area (SDN-POA) in male rat exhibits five to seven folds grater nucleus volume than that of females. During embryonic day (ED) 17-19, only male rat exhibits the testosterone peak, which prevented natural occurring neuronal apoptosis during postnatal day (PND) 7-10. Estradiol converted from testosterone plays an important role in the development of SDN-POA and protected SDN-POA neurons from apoptosis. However, molecular mechanism of testosterone in preventing SDN-POA neurons from apoptosis is still obscure. Previous report suggested that the estradiol treatment increased the number of NMDA receptor in the hippocampal neurons. Our previous results showed that the expression of NR1 subunit of NMDA receptor in POA of neonatal male rats is higher than that of females on PND 1 and PND 3. Since blockage of NMDA receptor by MK-801 enhances the neuronal apoptosis in the developing brain, such as CA1 hippocampus, thalamus, ventromedial hypothalamus and cortex, it is possible that the prenatal testosterone may prevent SDN-POA neurons from apoptosis through mediating the NMDA receptors.
In order to know the mechanism of testosterone exposure in affecting the morphological changes and expression of MNDA receptor, the prenatal testosterone peck was simulated or diminished artificially. Four groups of rats: (1) intact male (2) androgen sterilized (ASR) female (3) prenatal stressed (PNS) male and (4) intact female were designed. Serum level of testosterone was confirmed by RIA at ED 18. The density, nuclear volume, total neuron number, ratio of pykonsis in SDN-POA were estimated at PND 8. Apoptotic incidence in SDN-POA was estimated after TUNEL staining. Protein and mRNA expressions of NR1 and NR2D were quantified by Western blot analysis and RT-PCR, respectively. The results show that: (1) The testosterone level of intact male rat at ED 18 was significantly higher than that of intact females and the testosterone level was successfully diminished or simulated by prenatal stress or androgen sterilized, respectively. (2) The expression of NR1 protein in male rats was significantly higher than that of females, and the protein expression of NR1 in ASR female or PNS male rats was similar to intact male or intact female, respectively. No significantly differences of NR1 mRNA observed among intact male, ASR female, PNS male and intact female. (3) The protein and mRNA expressions of NR2D in male rat were significantly higher than that of females, whereas the protein and mRNA expressions of NR2D in ASR female or PNS male were similar to that of intact male or intact female, respectively. (4) No significant difference of neuronal density in SDN-POA neurons among the intact male, ASR female, PNS male or intact female was observed. The nuclear volume and total neuronal number in intact male were higher than that in intact female rats respectively, whereas no significant difference of nuclear volume or total neuronal number was observed between the ASR female and the intact male or between the PNS male and the intact female. The pyknotic ratio of intact male rats was significantly lower than that of females. In the intact male, the ratio of pykonsis was increased by prenatal stress while in the intact female; the ratio of pykonsis was decreased when prenatal testosterone was simulated by androgen sterilization. (5) Apoptotic incidence in intact female rats was higher than that of intact males, and the apoptotic incidence of ASR female or PNS male rats was similar to that of intact male or intact female, respectively. These results suggest that the prenatal testosterone exposure contribute to sexual difference in SDN-POA neurons and expression of NMDA receptor. Furthermore, the role of NMDA receptor in protecting neurons in the SDN-POA of male rat from apoptosis was studied by using MK-801, which is a non-competitive NMDA receptor open channel blocker. Rats were divided into four groups: (1) intact male (2) MK-801 treated male (3) intact female (4) MK-801 treated female. Apoptotic incidence in SDN-POA was evaluated after TUNEL staining at PND8. The result shows that: The apoptotic incidence of male rats on PND8 was significantly lower than that in females and was significantly increased when NMDA receptor was blocked by MK-801. However, no significant difference of apoptotic incidence between intact female and MK-801 treated female was observed.
These results suggest that the prenatal testosterone exposure prevented SDN-POA neurons from apoptosis through enhancing the expression of NMDA receptor.

略字表
一、 中文摘要 ……………………………………………………….4
二、 英文摘要 ……………………………………………………….7
三、 緒論 …………………………………………………………….10
四、 研究動機及實驗設計 …………………………………………16
五、 實驗材料與方法 ………………………………………………17
六、 實驗結果 ………………………………………………………40
七、 討論 ……………………………………………………………45
八、 參考文獻 ………………………………………………………50

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