面對威脅性或有害的刺激時，產生恐懼表現、自我防衛行為及適時地消除恐懼，將有利於個體的生存。帕弗洛夫恐懼制約與恐懼消滅 (Pavlovian fear conditioning and extinction) 為科學研究中最為廣泛使用的行為模型，儘管近年來對於恐懼記憶的習得已有很大的進展，然而，對於個體是如何學習恐懼記憶的消滅，仍有許多待解之處。另一方面，近年來對於外側眼窩前額葉皮質 (lateral orbitofrontal cortex) 的研究指出其在連結型學習 (associative learning) 及情緒調控中扮演重要角色，外側眼窩前額葉皮質的正常活性，更與精神疾病的發生息息相關。在這一系列的實驗中，我們利用此恐懼制約與恐懼消滅行為模型，並結合藥理學的方式，來探討外側眼窩前額葉皮質的活性對於習得恐懼消滅的影響。動物在恐懼制約訓練後的隔天進行恐懼消滅的學習，並在此隔天，進行學習表現的測試，我們在恐懼消滅學習前透過雙側微注射 N-甲基-D-天門冬氨酸 (N-Methyl-D-aspartic acid, NMDA) 來達到活化動物的外側眼窩前額葉皮質的目的，透過此一實驗，我們發現在動物學習恐懼消滅前活化外側眼窩前額葉皮質，會使動物在即便沒有恐懼制約刺激的出現下，都展現出一開始低、並隨時間逐漸升高的恐懼反應，同時也會使動物在學習測試時展現顯著高於控制組的恐懼表現，顯示這樣的操弄將會使恐懼消滅的學習受損。接著，為了探討外側眼窩前額葉皮質產生前述作用的效力，我們透過單側活化的方式來予以檢視，我們在動物進行恐懼消滅學習前單側或雙側活化此腦區，結果顯示在只有右側外側眼窩前額葉皮質活化的情況下，動物的恐懼表現並不會如左側或雙側活化般受到影響，然而，即便右側活化的動物在恐懼記憶的提取上展現出和控制組相同的表現，在第三天學習測試時，先前有受到操弄的動物，都可以觀察出恐懼消滅學習受損的狀況。我們的實驗證實了外側眼窩前額葉皮質的活性確實在恐懼消滅的習得過程中扮演著重要的角色，提供了臨床研究對於精神疾病的共病性及暴露治療法重要的參考，另外，我們也意外的觀察到外側眼窩前額葉皮質可能存在著的功能側化現象，而這相當值得未來研究的關注。

Fear extinction is a pertinent ability for individuals to adapt to the ever-changing environment. In our study, we demonstrated that the active involvement of the lateral orbitofrontal cortex (lOFC) affected conditioned fear expression and impaired fear extinction. Animals were trained and tested for fear extinction with the Pavlovian fear conditioning and extinction paradigm. Immediately before fear extinction training, N-Methyl-D-aspartic acid (NMDA) was injected directly into the lOFC of the animals to engage the lOFC in the learning process. We found that this manipulation would lead to an initially low then gradually increased freezing behavior and impaired fear extinction acquisition in that the experimental groups could not perform as well as the control groups during extinction retrieval. We further explored the efficacy of this manipulation with unilateral lOFC activation. This led to a surprising reveal of a functional lateralization in that during extinction, the right lOFC activation did not affect fear expression, but the left and bilateral lOFC activation did. However, regardless of the side being activated earlier, all animals showed impaired extinction acquisition. This result is of great translational value, since the abnormal activity in the OFC has been reliably found in patients with anxiety disorder, especially the obsessive-compulsive disorder (OCD). In conclusion, our data suggested that the abnormal activation of the lOFC could act to disturb fear extinction acquisition.

中文摘要 I
Abstract II
致謝 III
Chapter 1 Introduction 1
1.1 Pavlovian fear conditioning and extinction 1
1.1.1 The amygdala 2
1.1.2 The medial prefrontal cortex 4
1.1.3 Fear extinction and post-traumatic stress disorder 4
1.2 The orbitofrontal cortex 5
1.2.1 Anatomy of the OFC 5
1.2.2 The OFC and emotion regulation 6
1.3 Hypothesis and specific aims 8
Chapter 2 Materials and Methods 9
2.1 Subjects 9
2.2 Surgery 9
2.3 Behavioral procedures 10
2.3.1 Apparatus 10
2.3.2 Acclimation 10
2.3.3 Pavlovian fear conditioning and extinction 10
2.3.4 Experimental designs 11
2.4 Behavioral pharmacology 11
2.5 Histology 12
2.6 Behavioral data analysis 12
Chapter 3 Results 13
3.1 Experiment 1: Pre-extinction activation of the bilateral lOFC 13
3.1.1 Histology and final group 13
3.1.2 Behavior 13
3.2 Experiment 2: Pre-extinction activation of the unilateral lOFC 14
3.2.1 Histology and final group 14
3.2.2 Behavior 15
Chapter 4 Discussion 17
4.1 lOFC and emotion regulation 17
4.2 The laterality phenomenon 19
4.3 Future directions 20
4.3.1 mOFC versus lOFC 20
4.3.2 Pathway-specific study 20
4.3.3 Systematic and cross-species analysis 21
Chapter 5 Conclusion 22
Chapter 6 Figures 23
References 27

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