創傷後壓力症候群（Posttraumatic stress disorder, PTSD）是一種複雜綜合症，可能在接觸危及生命的事件後發生。一些研究已經顯示了創傷後的疾病狀態會造成生理，情緒和認知失調。幾個證據表明，恐懼記憶異常可能在創傷後症候群的病理過程中具有極重要角色，含括過於強化的恐懼記憶和恐懼記憶的消退異常。前人研究顯示恐懼記憶不是固態的;恐懼記憶的形成會隨著時間的推移而變化。此外，先前的研究顯示，恐懼表達可以用腦電圖（EEG）特徵來表徵，並且與θ（4Hz）和γ（30-70Hz）活動具有強烈相關性。然而，創傷後病理性恐懼記憶的形成與潛在腦電圖特徵之間的關係仍然很大程度上未知。在本研究當中，我們假設創傷壓力暴露後，在創傷後壓力症候群動物模式中異常的恐懼記憶形成動態變化可以透過腦電圖量測來反映早期和晚期階段。
我們使用單一連續刺激壓力並配合腳電擊（single-prolonged stress ＆ footshock, SPS＆FS）之PTSD大鼠創傷症候群模式。此模式當中將動物約束2小時，而後強迫游泳20分鐘，之後將大鼠暴露於乙醚中直至失去意識，再將動物移至電擊箱中直至動物醒來，給予腳電擊（每分鐘2次電擊（1.5mA）其長度1秒（總共5分鐘，10次電擊））。為了量測創傷後動物模型中異常恐懼的時間變化，我們將動物再次暴露於創傷情境並同時進行腦電圖記錄，紀錄時間點可區分為早期（經歷創傷壓力後10、30分鐘、2、4、6小時）和晚期（經歷創傷壓力後1、3、7和14天）。我們的動物行為量測結果顯示SPS＆FS大鼠在連續恐懼消退試驗中恐懼未消退仍表現出持續的恐懼反應，而在動物行為實驗曠野實驗（Open field test，OF），舉臂式十字迷宮（Elevated plus-maze，EPM）和強迫游泳測試（Forced swimming test, FST）創傷動物表現更高的焦慮和抑鬱之PTSD表型。SPS&FS暴露後觀察腦電圖特徵：在早期階段（SPS&FS後10分鐘和30分鐘）觀察到恐懼表現與δ（0.5-4Hz），θ（5-8Hz）和γ（> 30Hz）的活動具有高度相關，而創傷壓力後2-4小時開始轉變為δ活動並持續至創傷壓力後第14天，此δ活動的增量大小與恐懼表達強度有正向相關。目前的動物模式結果顯示在創傷壓力暴露後，可藉由量測腦波變化顯示出恐懼記憶與時間變化相關性，並可區分出早期與晚期。基因表現分析和c-FOS蛋白標記亦顯示早期與晚期的變化性。異常恐懼的時間軸分析有助於說明創傷後壓力症候群中病理性恐懼記憶的形成與時間相關性，此研究結果有助於了解此種複雜綜合症的預後和治療。

Posttraumatic stress disorder (PTSD) is a complex syndrome, which may occur after life-threatening event exposure. Fear memory abnormalities may play a vital role in the pathological course of PTSD. It was indicated that fear memories are not rigid; the retrieval of fear memory may change over time. Furthermore, studies suggested that the theta (4Hz) activities highly correlated with fear expression. However, the relation between the pathological fear memory and potential brain wave features in PTSD remains largely unknown. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamic changes of abnormal fears in PTSD animal models could be reflected by local field potentials (LFPs) measurements in early and late phases.
In our study, we use a well-established modified single prolonged stress (SPS&FS) PTSD rat model. Animals were restrained for 2 hrs and followed by 20 mins forced swimming, after that rats were exposed to diethyl ether until lose consciousness, then animals are kept in conditioning chamber until they awake, foockshock was applied after awaking for fear conditioning. To characterize the temporal changes after traumatic stress exposure, we characterized brain wave features while context re-exposure with freezing behavior at early (10 mins, 30 mins, 2,4, 6 hrs) and late phases (day 1, 3, 7, and 14). Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety, depression, and anhedonia, and impaired fear extinction. Time-dependent inhibitory delta (0.5–4 Hz) activities were observed in early phases (10 and 30 mins post-SPS & FS), whereas continuous delta activities predominated 2 hrs after traumatic stress exposure and persisted until day 14, the magnitudes of delta activities correlated with fear levels. Besides, transcriptome-level gene analysis and c-Fos protein labeling also indicated the temporal phase differences from early to late phases.
The longitudinal profiling of abnormal fears with brain wave correlates may help illustrate the time-dependent pathological fear memory retrieval in PTSD and may also help find better intervention strategies for this complex syndrome.

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