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標題: | 急性壓力活化食慾素系統造成抗憂鬱效果 Acute restraint stress leads to antidepression by activating orexin neurons |
作者: | Hsiao-Yun Chiu 邱曉筠 |
指導教授: | 邱麗珠(Lih-Chu Chiou) |
關鍵字: | 食慾素,憂鬱,神經新生,強迫游泳試驗, Stress,Orexin,OX1 receptors,OX2 receptors,depression,neurogenesis,forced swimming test, |
出版年 : | 2012 |
學位: | 碩士 |
摘要: | 食慾素(orexins)系統,由內生性促效劑orexins A和B組成(或名為hypocretin 1 和2),及兩種受器OX1R及OX2R所組成,orexin 神經元位於下視丘。許多人類及動物研究指出食慾素與憂鬱症狀相關。先前我們的研究指出,給予小鼠急性關閉警迫壓力(acute restraint stress)會活化下視丘食慾素神經元。在本研究中,利用小鼠強迫游泳試驗(forced swim test; FST)觀察其不動行為(immobility)的表現,及利用免疫螢光染色(immunofluorescence),觀察海馬齒狀回(dentate gyrus)中神經新生(neurogenesis)的情形,計算doublecortin (一種不成熟神經細胞標記) 及BrdU (一種細胞分裂標記)正反應的細胞數目,探討由急性關閉警迫壓力所致的食慾素活化在緩解憂鬱行為中所扮演的角色。由結果得知,小鼠接觸三十分鐘的急性關閉警迫壓力後相較於控制組會減少強迫游泳試驗中不動行為的表現。腦室內給予(i.c.v.) 食慾素(1 nmol/0.5 μl/mouse)重現急性關閉警迫壓力所造成的影響,能夠減少強迫游泳試驗中不動行為的表現。在急性關閉警迫壓力前十五分鐘投予OX2R拮抗劑(Compound 29, 30 mg/kg, i.p.)而非OX1R拮抗劑 (SB-334867, 15 mg/kg, i.p.),能回復急性關閉警迫壓力及腦室投予食慾素所造成不動行為減少的影響。OX1R拮抗劑及OX2R拮抗劑單獨作用在未施與壓力的小鼠皆不會影響其不動行為的表現。此外,腦室內投藥所造成的壓力能減少不動行為的表現,且此表現不會對OX1R拮抗劑及OX2R拮抗劑影響。急性關閉警迫壓力會增加海馬齒狀回齒狀迴顆粒細胞下區(subgranular zone of the dentate gyrus)中同時有BrdU及doublecortin正反應的細胞數目。這些結果暗示急性關閉警迫壓力活化下視丘食慾素神經系統活化OX2R造成抗憂鬱作用,此外,由腦室內投藥引起的壓力所造成的抗憂鬱作用則與食慾素無關。 The orexin system, consisting of orexin A and B and OX1R and OX2R, has been reported to be associated with depression in both human and animal studies. Orexin-containing neurons are limitedly localized in the hypothalamus. Previously, we found that acute restraint stress can activate hypothalamic orexin neurons. Here, we examined if the orexin system activated by restraint stress plays a role in relieving the depressive behavior in mice, immobility in the forced swimming test (FST), and hippocampal neurogenesis, which was measured by the number of cells double-immunoreactive to doublecortin (a neuronal marker) and BrdU (a cell proliferation marker) in the subgranular zone of the dente gyrus. Mice subjecting to restraint stress for 30 min showed significantly shorter immobility time in the FST than un-restrained mice. Orexin A (1 nmol/0.5 μl/mouse, i.c.v.) reproduced the effect of restraint stress, i.e. significantly shorter immobility time in un-restrained mice. Pretreatment with the antagonist of OX2 receptors (Compound 29, 30 mg/kg, i.p.), but not that of OX1 receptors (SB-334867, 15 mg/kg, i.p.), for 15 min significantly restored the immobility time in restrained mice and that in i.c.v. orexin-treated un-restrained mice. Both antagonists alone had no effect on the immobility time in un-restrained mice. The FST immobility time in the vehicle group by i.c.v. injection was shorter than by i.p. injection and this difference was not affected by either OX1R or OX2R antagonist. Restraint stress increased the number of BrdU/doublecortin double-immunorective cells in the subgranular zone of the dente gyrus. These results suggest that acute restraint stress results in activation of hypothalamic orexin neurons, releasing orexins which induce an antidepressant-like effect mediated through OX2 receptors. The stress induced by i.cv. procedure also decreased the FST depressive behavior, but this antidepressant effect is orexin-independent. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15901 |
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