||MicroRNA-206 regulates stress-provoked aggressive behaviors in post-weaning social isolation mice
||Department of Pharmacology
||Elizabeth Joo-Wen KueK
當遇到急性壓力時，社交孤立（Social Isolation, SI）小鼠的情緒狀態將最終導致防禦行為的異常表現並誘發攻擊行為，這讓人聯想到人類的反應性衝動性攻擊。我們以前已經證明，腹側海馬體（Ventral Hippocampus, VHip）內的腦源性神經營養因子（Brain derived neurotrophic factor, BDNF）對於斷奶後社會隔離（post-weaning social isolation）小鼠的應激激發攻擊行為至關重要。然而，壓力引發攻擊的原因和潛在機制仍然難以捉摸。在這裡，我們研究了BDNF在VHip的表觀遺傳（epigenetic）調控。在出生後第21-28天，將小鼠隨機分配成五隻一籠或單隻一籠中飼養5週。我們發現與群居（Group Housing, GH）小鼠相比，SI小鼠表現出更高水平的microRNA 206（miR-206）。先前的研究表明，miR-206可以調節阿爾茨海默病（Alzheimers’disease）轉基因小鼠中的BDNF，該小鼠由AM206以劑量依賴性方式拮抗。定量PCR（qPCR）顯示，海馬內註射AM206降低了SI誘導的miR-206和攻擊數量的增加而不影響運動活性。同時，AM206增加BDNF的mRNA和蛋白質水平。此外，結果還表明，在使用shRNA減少BDNF的表現量後逆轉了SI小鼠中AM206的作用，但並不影響GH小鼠。除此之外，通過在GH小鼠中使用慢病毒模擬miR-206，結果顯示與對照組相比，GH小鼠中過度表達miR-206顯著的增加了其攻擊次數。因此，我們的結果表明了AM206具有潛在治療壓力加劇攻擊性行為的效果。
When encountered acute stress, the emotion state of socially isolated (SI) mice will culminate in aberrant expressions of defensive behaviors and induced outburst of attack behavior which was reminiscent of reactive-impulsive aggression in humans. We have previously shown that brain derived neurotrophic factor (BDNF) within the ventral hippocampus (VHip) was critical for stress-provoked aggressive behaviors in the post-weaning social isolation mice. However, the causes and underlying mechanism of stress-provoked aggression remain elusive. Here, we investigated the epigenetic regulation of BDNF in the VH. At postnatal day 21–28, mice were randomly assigned to a group or isolated cages for 5 weeks. We found that the isolated (SI) mice exhibited a higher level of microRNA 206 (miR-206) compared to group housing (GH) mice. Previous study has shown that miR-206 can regulate BDNF in transgenic mice of Alzheimer disease that was antagonized by AM206 in a dose-dependent manner. Quantitative real-time PCR (qPCR) showed that intra-hippocampal injection of AM206 decreased SI-induced increase in miR-206 and attack numbers without affecting locomotion activity. In parallel, AM206 increased both mRNA and protein levels of BDNF. Furthermore, the results also demonstrated that after knockdown BDNF reversed the effects of AM206 in the SI mice but did not affect the GH mice. Besides that, by using lentivirus mimic miR-206 in the GH mice, the results showed that overexpression miR-206 in the GH mice significantly increased the number of attacks compared with the control group. Therefore, our results suggest a potential therapeutic effect of AM206 against stress exacerbation of aggressive behaviors.
Abstract in Chinese...I
Abstract in English...III
List of Figures...IX
Early life stress...3
Post-weaning social isolation...3
The neural mechanism of aggression...4
Materials and Methods...10
Figures and Legends...37
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