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論文名稱(外文):NMDA receptor blockade in the hippocampus improves the post-weaning social isolation-induced emotional dysfunctions
指導教授(外文):Po-Wu Gean
外文關鍵詞:social isolationaggressionNMDA receptoracute stresseEF2BDNF
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已知早年的社會環境是發展憂鬱症或精神分裂症等神經心理疾病的潛在因子之一。在神經心理疾病患者常可觀察到突發性的攻擊行為，然而暴力行為相關的神經研究仍屬少見。本篇研究欲利用斷奶後早年社會隔離(post-weaning social isolation)的動物模式來探討在成年後所發展出的異常暴力行為以及如何利用藥物減緩暴力行為的發生。在本實驗建立的動物模式裡可觀察到早年隔離小鼠在成年後出現過動、前刺激抑制聲音驚嚇反射(prepulse inhibition of acoustic startle reflex, PPI)缺損和似憂鬱行為表徵。而在攻擊行為測試中，相較於群居小鼠，隔離小鼠只表現較多的威嚇行為，而無直接的咬嚙攻擊。如進一步給予急性壓力，則可發現隔離小鼠會明顯用咬的攻擊BALB/c小鼠以及在open field測試裡更為焦慮。此實驗結果表示在早年社會隔離後，在成年時面對急性壓力的反應更為強烈，易出現攻擊和焦慮行為。此外，隔離小鼠的海馬迴也發現神經突觸表面NR2A和NR2B有明顯增多。利用腦顯微手術將MK-801(NMDA-R抑制劑)或是ifenprodil (NR2B專一抑制劑) 在急性壓力前注入隔離小鼠的海馬迴內，結果發現除了能減緩隔離小鼠的憂鬱症狀且能明顯減少異常攻擊行為；而利用shRNA技術減少海馬迴內的NR2B蛋白表現後，也發現隔離小鼠的攻擊行為明顯下降。實驗結果顯示早年社會隔離所造成的海馬迴內NMDA-Rs異常增加會導致成年後面臨壓力時易出現異常的暴力行為。此外，隔離小鼠海馬迴內的磷酸化eEF2也比群居小鼠多，急性壓力則促使更多的磷酸化eEF2，此現象與隔離小鼠面臨壓力時易出現暴力行為極為相符；而MK-801會促使eEF2去磷酸化，增加eEF2活性，並提升海馬迴內BDNF蛋白的表現；在急性壓力前注入eEF2激酶抑制劑於海馬迴內能減緩憂鬱症狀和異常攻擊行為，並促使BDNF蛋白表現量增加，此與MK-801的效果相同；而利用shRNA技術減少BDNF蛋白的表現，則使得MK-801和eEF2激酶抑制劑的效果消失，因此可知MK-801抑制攻擊行為的效果來自於eEF2活性的增加，促使提升海馬迴內BDNF蛋白的表現。總結上述的實驗結果，社會隔離使得小鼠海馬迴內的NMDA受體增加，促使面對壓力時易有攻擊行為，NMDA受體抑制劑能減緩憂鬱症狀和異常攻擊行為，其分子機轉來自於活化海馬迴內的eEF2和BDNF。
Accumulating epidemiological evidence shows that early life events have long-term effects on the susceptibility to subsequent stress exposure during adulthood. Here we reported the effects of post-weaning social isolation, an animal model of early life adversities, on the behavioral responses to acute stress in adult mice. At postnatal day 21, mice were randomly assigned to group housing (GH) or individual cages for 8 weeks and behavioral tests were performed at the age of 3 months. Socially isolated (SI) mice exhibited higher spontaneous locomotor activity, depression-like behavior, impaired sensorimotor gating and more aggressive behavior but not attack number. Moreover, acute stress significantly exacerbated attack counts of SI mice to the intruder BABL/c mice and induced higher levels of anxiety-like behavior in the SI mice than in GH mice. In addition, post-weaning social isolation increased hippocampal surface expression of NR2A and NR2B subunits. Bilateral hippocampal infusion of the NMDA antagonist, MK-801or ifenprodil, reversed stress-induced attack behavior in the SI mice. Moreover, the specific knockdown of NR2B expression in the hippocampus by shRNA transfection technique significantly reduced the stress-induced attack level of SI mice. Thus, the increased levels of NMDA-Rs in the hippocampus may be responsible for the post-weaning social isolation-induced emotional alterations. Additionally, SI mice exhibited an increased level of eEF2 phosphorylation in the hippocampus and acute stress induced even higher levels of eEF2 phosphorylation. This corresponds to the stress-induced outburst of attack behavior in SI mice. Furthermore, NMDA-R blockade increased the eEF2 activity and induction of BDNF expression in the hippocampus. Microinjection of eEF2 kinase (eEF2K) inhibitors into ventral hippocampus mimicked MK-801-induced anti-aggressive response and increased BDNF expression. Knockdown of BDNF expression in the hippocampus blocked the behavioral effects of MK-801 and eEF2K inhibitor. Thus, anti-aggressive effects of MK-801 are mediated through the increased eEF2 activity, leading to induction of BDNF expression. Conclusion: These results suggested the isolation-induced increased levels of NMDA receptors in the hippocampus may mediate the stress-induced aggression. NMDA-R blockade reduces the attack and depression-like behavior, which requires the activation of eEF2-BDNF pathway. Our findings could yield novel therapeutic targets for aggression.
Abstract in Chinese...........1
Abstract in English..........4
List of figures ...........10
Chapter 1: Introduction..........15
The aims of the research............24
Chapter 2: Materials and methods........26
Chapter 3: Post-weaning social isolation induces abnormal phenotypes in relative to symptoms of neuropsychiatric disorders..............36
Chapter 4: Post-weaning social isolation induces an increased NMDA-R level in the hippocampus.....41
Chapter 5: The activation of the eEF2-BDNF pathway is required for the anti-aggressive effect of NMDA-R blockade ...................52
Chapter 6: Discussion and prospect........63
Future perspectives ...........72
Figures and Legends..........89
Curriculum vitae .............122
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