臺灣博碩士論文加值系統

根據世界衛生組織2017年的統計，已超過3億人飽受憂鬱症之苦。基因遺傳與環境皆是造成憂鬱症的風險因子，而我們的研究所關注的是環境因子，環境因子包含了醫療疾病、藥物濫用，以及壓力事件。在病理上，憂鬱症與前額葉皮質有著重要的關聯性。前額葉皮質為調節情緒的主要腦區，在病人上可以觀察到前額葉皮質的神經細胞減少，以及glutamate相關的功能受損。最近的研究指出麩胺酸受體亞型N-甲基-D-天冬氨酸受體(N-methyl-D-aspartate receptor, NMDAR) 在抗憂鬱上扮演重要的角色，且與α-氨基-3-羥基-5-甲基異惡唑-4-丙酸(alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor, AMPAR)有關。然而，前額葉中調控著NMDAR活性對於情緒處理上扮演之角色仍是未知。在本研究中，我們以慢性社交挫敗壓力動物模式(chronic social defeat stress, CSDS)作為憂鬱症的模型，來探討NMDAR 作為抗憂鬱的目標的潛力。我們的結果顯示，在自發境運動測試(Open field test)以及高舉十字迷宮(Elevated plus maze)的行為測試上，憂鬱鼠表現出焦慮的行為表現，在尾部懸吊實驗(Tail suspension test)、強迫游泳試驗(Forced swimming test)，以及糖水喜好性測試(Sucrose preference test)，憂鬱鼠表現出憂鬱的行為表現。為進一步探討NMDAR在抗憂鬱中所扮演的角色，我們使用了NMDA receptor的拮抗劑Ketamine。結果顯示，Ketamine可改善憂鬱的行為表現，並改善AMPAR 中的GluR1、GluR2，和突觸蛋白PSD95的減少狀況，而長期增益效應(long-term potentiation, LTP)的受損及突觸的減少也都在Ketamine的治療後得到改善。根據上述結果，我們可以得知，NMDAR在抗憂鬱治療上，是一個有潛力的目標的機制。

The World Health Organization estimates that more than 300 million individuals of all ages suffer from depression in 2017. Genetic and environmental factors are associated with the risk factor and the outcome of depression. In our study, we focus on environmental factors, such as medical illness, drug abuse and stressful events. In pathology, the prefrontal cortex (PFC) which is a critical to regulating emotion has been shown to have significant roles in depression. In patients, several studies had indicated reduced neuronal cell and glutamate related function in PFC. Recent studies demonstrate that glutamatergic N-methyl-D-aspartate (NMDA) receptor exhibits an important role of antidepressant effects which mediated by alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor. However, the regulation of synaptic NMDA receptors activity within PFC in emotional processing was remaining unclear. In this study, we used the chronic social defeat stress (CSDS), which is a depression model, to investigate the potential of NMDA receptor as an antidepressant target. In open field test and elevated plus maze, the results showed the anxiety-like behaviors in depression model mice. And the depression model mice showed the depressive-like behaviors in tail suspension test, forced swimming test and sucrose preference test. To investigate the role between antidepressant effect and NMDA receptor. We used the ketamine which is a NMDA receptor antagonist. The results showed that the depressive-like behavior was treated by ketamine. The reduction of AMPA receptor subunits GluR1, GluR2 and synaptic protein PSD95 were reversed by ketamine. The impairment of long-term potentiation (LTP) and the reduction of spine density were reversed by ketamine treatment. These results suggested that modulation of NMDA receptor is a potential antidepressant target in treating depression.

誌謝 I
摘要 II
Abstract III
Contents IV
List of Figures V
Introduction 1
Materials and Methods 8
Results 19
Discussion 23
Summary 27
References 28
Figures 38

List of Figures
Figure 1. Overview of the chronic social defeat stress 39
Figure 2. Mice subjected to CSDS colud be separated into susceptible and resistant subpopulations 40
Figure 3. The susceptible group showed the anxious behavior in open field test 41
Figure 4. The susceptible group exhibited the anxiety-like behavior in elevated plus maze (EPM) 42
Figure 5. The susceptible group showed the depression-like behaviors 43
Figure 6. Ketamine treatment ameliorated CSDS-induced depressive like behavior 44
Figure 7. Reduction of GluR1 and GluR2 protein level could be reversed by Ketamine treatment within the prefrontal cortex in the susceptible mice 45
Figure 8. Reduction of PSD95 protein level could be reversed by Ketamine treatment within the prefrontal cortex in the susceptible mice 46
Figure 9. The susceptible mice reduced synaptic plasticity of LTP and reversed by ketamine treatment in prefrontal cortex 47
Figure 10. The susceptible mice exhibited decreased dendritic spine and was reversed by ketamine treatment 48
Figure 11. Reduction of mTOR protein phosphorylation level could be reversed by Ketamine treatment within the prefrontal cortex in the susceptible mice 49
Figure 12. Reduction of p70S6K and S6 protein phosphorylation level could be reversed by Ketamine treatment within the prefrontal cortex in the susceptible mice 50
Figure 13. Reduction of 4EBP1 protein phosphorylation level could be reversed by Ketamine treatment within the prefrontal cortex in the susceptible mice 51

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