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研究生:翁婉容
研究生(外文):Wan-Rong Wong
論文名稱:以思覺失調症候選基因Akt1缺陷小鼠探討新生期聚肌胞酸刺激對新生期免疫反應與成鼠行為之影響
論文名稱(外文):The effect of neonatal poly(I:C) exposure on neonatal immune responses and adult behavioral consequences in Akt1 deficient mice
指導教授:賴文崧賴文崧引用關係
指導教授(外文):Wen-Sung Lai
口試委員:梁庚辰黃憲松薛一蘋蔡惠珍
口試委員(外文):Keng-Chen LiangHsien-Sung HuangYi-Ping HsuehHey-Jen Tsay
口試日期:2014-07-10
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:腦與心智科學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:140
中文關鍵詞:思覺失調症Akt1基因缺陷小鼠新生期免疫活化聚肌胞&;#33527;酸細胞激素微膠細胞小鼠行為作業
外文關鍵詞:schizophreniaAkt1 mutant miceneonatal immune challengepoly(I:C)behavioral phenotypingcytokinesmicroglia
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Schizophrenia appears to be a multifactorial disorder with a strong genetic predisposition. Accumulating evidence suggests Akt1 (also known as protein kinase Bα) may contribute to susceptibility to schizophrenia. Akt1 knockout mice also exhibited some behavioral impairments and neuromorphological abnormalities. In addition to genetic predisposition, early infection-induced disruption in neurodevelopment may lead to functional deterioration and the onset of schizophrenia in later life. Indeed, immuno-precipitated neurodevelopmental animal models displayed aberrant behavioral functions. An alteration of Akt1 expression was also observed in prenatal immune challenged mice. Given the existing evidence, the objective of this study is to examine the effect of early infection alone and its interaction with Akt1 deficiency on the alterations of neonatal immune responses and schizophrenia-related neurobehavioral functions in adulthood. Akt1 heterozygous pups and their wild-type littermate controls received daily injections of polyriboinosinic-polyribocytidylic acid (poly(I:C)) from postnatal days 2 to 6 to induce antiviral responses. Their neonatal immune responses and adult behavioral consequences were evaluated in three experiments. In Experiment 1, using a cytometric bead array, our cytokine analysis revealed an alteration of TNF-α level in female Akt1 deficient pups compared to wild-type controls after poly(I:C) challenge. In Experiment 2, Iba1 immunohistochemistry was used to label microglia in the mouse brains. Our data exhibited an enlargement of microglia size or an increased expression of Iba1+ cell numbers in Akt1-deficient neonatal mice with neonatal poly(I:C)-challenge, especially in the thalamus and the periaqueductal gray region of female mice. In Experiment 3, a battery of behavioral tasks, including open field, Y maze, social preference, social recognition, USVs playback approaching paradigm, tail suspension, and prepulse inhibition, were conducted in adult mice three months after neonatal poly(I:C) challenge. The overall behavioral phenotyping results indicated that neonatal poly(I:C) challenge appeared to have minor long-term impacts on behavioral performances. A sex-specific interaction between genotype and poly(I:C) challenge in social recognition was found in adult male mice. We also found that Akt1 deficient females with neonatal poly(I:C) challenge also displayed an impairment of sensorimotor gating function. Our data indicated that neonatal poly(I:C)-induced immune response can be altered by Akt1 deficiency but neonatal poly(I:C) exposure has minor impacts on adult behavioral performance. This study suggested a possible association among Akt1, TNF-α and microglia in the pathogenesis of schizophrenia-related phenotypes.

致謝 iii
摘要 v
Abstract vii
Table of Contents ix
Tables and Figures xii
Chapter 1. Introduction 1
1.1 An overview of schizophrenia 1
1.1.1 What is schizophrenia? 1
1.1.2 Symptoms of schizophrenia 2
1.1.3 Gender differences in schizophrenia 5
1.2 Etiology of schizophrenia 6
1.2.1 Neurotransmitter hypotheses of schizophrenia 6
1.2.2 Neurodevelopmental hypothesis of schizophrenia 7
1.2.3 Risk factors of schizophrenia 8
1.2.4 Modeling schizophrenia in animals 10
1.3 Akt1 as a genetic factor of schizophrenia 12
1.3.1 What is Akt1? 12
1.3.2 Genetic evidence of Akt1 in schizophrenia 14
1.3.3 Animal models of Akt1 deficiency 15
1.4 Early-life immune activation as an environmental factor of schizophrenia 17
1.4.1 Epidemiological evidence of early-life infection in schizophrenia 17
1.4.2 Modeling early-life infection in animal models 19
1.4.3 Microglia as an inflammatory component in early-life infection 22
1.4.4 Cytokines as inflammatory components in early-life infection 26
1.4.5 Different administration time of immune stimulants lead to different consequences 30
1.5 Objectives of this study 32
Chapter 2. Materials and methods 37
2.1 General materials and methods 37
2.2 Experiment 1: Measurement of pro-inflammatory cytokines 38
2.3 Experiment 2: Immunohistochemical detection of microglia 40
2.4 Experiment 3: Adult behavioral phenotyping 41
2.5 Statistical analyses 47
Chapter 3. Results 49
3.1 Experiment 1: Cytokine expression in neonates 49
3.2 Experiment 2: Microglia activation in neonatal brains 52
3.3 Experiment 3: Behavioral phenotyping in adult mice 55
Chapter 4. Discussion 63
4.1 Summary of results 63
4.2 Altered cytokine levels in the neonatal brain—with a focus on TNF-α 64
4.3 Microglia activation— linking Akt1, TNF-α, and schizophrenia 67
4.4 Comparing results of behavioral phenotyping with previous studies 70
4.5 Sex differences in immune response and behavioral phenotypes 73
4.6 Limitation of this study 74
4.7 Contribution and possible application 75
Tables and figures 81
References 111


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