臺灣博碩士論文加值系統

青春期遭遇性騷擾(sexual harassment)、學校霸凌(bullying)、情感虐待(psychological abuse)和家庭暴力(domestic violence)等創傷經驗會導致心理創傷(psychological trauma)，已被證實會對心理健康產生長期的不良影響，並增加成年後罹患精神疾病的風險。不幸的是，針對其不良影響的發生，目前僅有少數研究與有限的治療策略。本研究之主要目的為利用青春期綑綁處理動物模式(juvenile immobilization treatment, J_IMO)模擬青少年期創傷經驗，以探究其對海馬迥功能(hippocampal function)的不良影響及其神經機。
本研究採用C57BL / 6J品系雄性小鼠，在出生後第35天和第36天(postnatal day, PND)時進行每天一次2小時，共兩天的J_IMO處理。於第二次綑綁處理後一週時(PND-42)分別進行行為(behavioral)、電生理(electrophysiological)和生化(biochemical)實驗。行為實驗採用抑制迴避測試(inhibitory avoidance, IA) 來評估海馬迴(hippocampus)的學習記憶功能，IA為一與海馬迥功能高度相關的記憶試驗。我們也利用開放空間測試(open field test, OFT)和高架十字迷宮測試(elevated plus-maze test , EPM)來評估J_IMO的類焦慮行為(anxiety-like behavior)。部分動物則斷頭犧牲取腦，製成海馬迴腦切片用於離體胞外電生理記錄(in vitro extracellular recording)，以高頻電刺激(high-frequency stimulation, HFS)誘發的長期增益效應(long-term potentiation, LTP)，來評估動物海馬迴的神經可塑性(neuroplasticity)。為了防止行為實驗對生化分析所造成之干擾，我們以相同的方式準備了另外一批動物，於PND-42時斷頭犧牲，取出其海馬迴進行即時定量聚合酶連鎖反應(real-time polymerase chain reaction, qPCR)分析Grin2a （NR2A受體），Slc12a2 （鈉鉀氯共轉運蛋白2，又簡稱NKCC1），Slc12a5 (鈉鉀氯共轉運蛋白5，又簡稱KCC2), Gabra1（GABAA受體）和Fkbp5（co-chaperone with the heat shock protein 90 and steroid complex）等基因的表現，並且利用西方墨點法（Western blot）來確認NKCC1的蛋白質表現量。
實驗結果顯示，經 J_IMO處理的小鼠，其抑制性迴避學習增強，合併出現削減學習(extinction learning)減弱的現象。而OFT的結果顯示J_IMO組的類焦慮行為有增加的情形，然而在EPM中並未獲得一致的結果。J_IMO組動物的海馬迴HFS-LTP有增強的現象，與對照組相較經J_IMO處理小鼠的輸入和輸出曲線比值（input/output curve ratio, I/O curve）中出現顯著增加的現象。而在配對脈衝促進（pair-pulse facilitation. PPF）的結果並無顯著差異。這些結果暗示海馬迴HFS-LTP的增強應是源自突觸後的機制(post-synaptic mechanism)，例如受體表現量增加(up-regulation)，或者信號傳遞活性增強。qPCR的結果顯示，經J_IMO處理小鼠海馬迴中Grin2a和Slc12a2的表現量顯著增加，可以證明J_IMO組海馬迴突觸後的機制改變。Fkbp5，Slc12a5和Gabra1的表現量未呈顯著差異。之後，我們以表面灌流(suprafusion)方式投予兩種環形利尿劑(loop diuretics)，呋塞米(furosemide)或布美他尼(bumetanide)為NKCC1抑制劑，可將海馬迴HSF-LTP恢復至正常範圍。綜合各項實驗結果，經過J_IMO處理的小鼠表現出異常的行為表現，包括迴避學習之增強、消減學習(extinction learning)能力減弱，和類焦慮行為的增加。J_IMO組的海馬迴HSF-LTP增強海，馬迴功能相關基因如Grin2a，Slc12a2的表現量明顯改變。這些結果共同顯示出，給予J_IMO急性處理也可能對海馬迴功能產生長期影響。
本研究結論為J_IMO處理成功地模擬了青少年的創傷經歷，並且產生長期的不良影響，這和前人之成年IMO處理的研究發現是一致的。有趣的是，我們發現NKCC1在J_IMO小鼠中的海馬迴表現量發生了變化，這解釋J_IMO治療處理不良反應的可能機制。我們建議NKCC1抑制劑如布美他尼可以作為治療藥物，以減輕青少年創傷事件引起的行為異常。

Traumatic events during adolescence such as sexual molest, school bullying, emotional abuse, and domestic violence might result in psychological trauma and a long-term deleterious effect on mental health. They would eventually increase the risk of having psychiatry diseases in the adulthood. Unfortunately, the detailed related neural mechanism remains unclear, and limited therapeutic strategies are available to prevent the adverse consequences. Here, a modified juvenile immobilization treatment (J_IMO) animal model was applied to investigate the neural mechanism underlying the adverse effect of juvenile traumatic events on the function of the hippocampus. Briefly, C57BL/6J mice received J_IMO treatment at the postnatal day 35 and 36 (PND). One week later (PND-42), they were subjected to behavioral, electrophysiological, and biochemical experiments. We evaluated the hippocampal function by using an inhibitory avoidance test (IA), a well-known hippocampus-dependent memory task. The anxiety-like behaviors were examined by the open field test (OFT) and elevated plus-maze test (EPM). We also used the in vitro extracellular recording to study the high-frequency stimulation-induced long-term potentiation (HFS-LTP) of the hippocampus. Furthermore, the expression of anxiety-related genes such as Grin2a (NR2A receptor), Gabra1 (GABAA receptor), Slc12a2 (sodium potassium chloride cotransporter-1, NKCC1), Slc12a5 (potassium-chloride transporter member 5, KCC2), and Fkbp5 (co-chaperone with the heat shock protein 90 and steroid complex, FKBP5) of the six weeks old J_IMO mice was determined by using real-time polymerase chain reaction (qPCR) and western blot.
Results showed that enhanced avoidance learning in the J_IMO treated mice. Also, the J_IMO-treated male mice displayed some degree of interference on the extinction of the IA task. Furthermore, an elevation of anxiety-like behavior was revealed in the test of OFT. The hippocampal HFS-LTP increased in the J_IMO treated group, which could explain the enhanced avoidance learning. A significant difference was found only in the input-output curves (I/O curve), but not in the pair-pulse facilitation (PPF), between control group and J_IMO treated mice. These results implied the enhanced hippocampal HFS-LTP was resulted from a postsynaptic mechanism such as increased receptor expression, or an increase of signal transduction activity. Our qPCR results showed that the expression of Grin2a and Slc12a2 were increased significantly, On the contrary, the expression of Fkbp5, Gabra1 and Slc12a5 were not significantly altered in the J_IMO treated mice. Administration of loop diuretics furosemide or bumetanide, NKCC1 inhibitors, restored the hippocampal HSF-LTP to the normal range.
Based on our findings, the J_IMO treated mice actually revealed certain abnormal behavioral phenotypes, including a deficit in the extinction of avoidance learning, an increase in anxiety-like behavior, the enhancement of hippocampal HSF-LTP, and a significant upregulation of anxiety-related genes, Grin2a and Slc12a in hippocampus. These results collectively indicated that even an acute J_IMO treatment might elicit a long-term impact on hippocampal functions.
Conclusively, the J_IMO treatment designed in this study has successfully simulated the juvenile traumatic experience, and has provoked a long-term deleterious impact consistent to the previous finding in adult IMO model studies. It is worth noting that the hippocampal expression of NKCC1 was altered in the J_IMO mice, and that might account for the long-term adverse effect of J_IMO treatment. Accordingly, the NKCC1 inhibitor bumetanide might become a therapeutic agent to relieve the behavioral abnormalities induced by juvenile traumatic events.

INTRODUCTION 1
Adverse juvenile experiences and the associated long-term impact 1
Anxiety disorder and the dysfunction of the HPA axis 2
Brain structures correlated to the stress-induced behavioral abnormalities 5
Glucocorticoid effects on the function of the hippocampus 6
The related genes for stress-induced behavioral abnormalities related genes 8
The impact of stress on the excitatory neurotransmission 10
Stress-induced abnormality of cation-coupled chloride transporters (CCCs) 11
Research aim and significance 14

MATERIALS AND METHODS 15
Animals 15
Juvenile immobilization treatment (J_IMO) 15
Inhibitory avoidance test (IA) 16
Open field test (OFT) 17
Elevated plus-maze (EPM) 18
Brain slice extracellular recording 19
Administration of bumetanide and furosemide 20
Real-time polymerase chain reaction 21
Western blot 24
Statistics 25

RESULTS 27
Experiment-1: Examine the juvenile immobilization treatment effects on the inhibitory avoidance learning. 27
Experiment-2: Evaluation of the juvenile immobilization treatment induced anxiety-like behavior in the male mice by open field test and elevated plus-maze test. 30
Experiment-3: Determine the hippocampal long-term potentiation of the IMO animals using brain slice extracellular recording. 32
Experiment-4: Determine the input-output curve and paired-pulse facilitation of the brain slices of J_IMO treated animals. 34
Experiment-5: Examine the expression of HPA axis-related and neurotransmitter receptor genes of the hippocampal on the juvenile IMO animals by using real-time polymerase chain reaction. 36
Experiment-6: Analyze the hippocampal NKCC1 expression of J_IMO mice by Western blotting. 38
Experiment-7: The enhanced hippocampal HFS-LTP of the J_IMO animals were reversed by suprafusion of NKCC1 antagonist in a dose-dependent manner. 39

DISCUSSION 43
Summary of the results 43
The juvenile IMO treatment reveals an opposite effect on the acquisition and the extinction of inhibitory avoidance memory. 45
The high-frequency stimulation-induced hippocampal long-term potentiation is enhanced in juvenile IMO treated mice. 51
The involvement of NKCC1 in the J_IMO treatment effects on hippocampal function. 54
Conclusion 61

REFERENCES 63

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