思覺失調症為一嚴重的精神疾病且有著複雜的基因致病因素。在過去諸多研究中顯示，思覺失調症有明顯的性別差異，其中包含疾病盛行率、發病年齡、症狀以及對於藥物的反應。然而思覺失調症之性別差異的分子機轉至今仍未被詳細的研究，此類研究可提供重要的資訊，使思覺失調症進一步的被瞭解。在不同族群的人類基因研究中，AKT1 (protein kinase B α) 被發現與思覺失調症的致病機轉有關聯，為該疾病的候選基因之一。Akt1基因缺損小鼠被發現有類思覺失調症的特徵且展現出性別差異。除此之外，AKT1也是多巴胺受體D2的下游；AKT1的異常會導致多巴胺訊息傳遞鏈的缺損，進而引發行為上的異常。因此Akt1基因缺損小鼠是研究思覺失調症與其性別差異的合適動物模式。在本研究中的第一部分中，行為測驗被用於檢驗Akt1異形和子 (Akt1+/-) 小鼠的性別差異。行為測驗發現Akt1+/-公鼠表現較高的酬賞敏感度；母鼠則是對甲基安非他命有較高敏感度，但Akt1+/-母鼠相較於野生型母鼠(Wildtype)則對甲基安非他命有較低敏感度。為了要瞭解Akt1基因缺損小鼠的性別差異之分子機制，使用了次世代RNA定序 (RNA-sequencing) 去分析Akt1基因缺損小鼠的紋狀體之基因表現。基因表現量差異是使用DESeq2進行分析，發現帶有Akt1基因缺損後的公母鼠之間具有顯著表現量差異的基因數量變多 (WT♂vs. WT♀: 14 DE genes; Akt1+/-♂ vs. Akt1+/-♀: 322)。而相較於公鼠，母鼠表現出更多具有顯著表現量差異的基因 (WT♂vs. Akt1+/-♂: 18; WT♀vs. Akt1+/-♀: 119)。此外，有92個基因的表現量有顯著交互作用。基因功能分類(gene ontology)以及分子路徑 (pathway analysis) 分析結果顯示公鼠 (WT♂vs. Akt1+/-♂) 中受到Akt1基因缺損影響的生物性功能為免疫以及細胞間交互作用 (cell-cell interaction)，而母鼠 (WT♀vs. Akt1+/-♀) 則是mRNA (messenger RNA) 相關調控機制則是受到最顯著的影響。最後，RT-qPCR結果顯示，Akt1+/-母鼠表現出較高的予基因轉錄現象有關的基因 (Hipk3, Ankrd10, Map4k5)。除此之外，在多巴胺相關 (Prprn2, Tspan7) 及Akt/Akt1相關 (Cadm2, Bmi1, Lnp) 的基因表現量上亦有顯著的性別差異。本篇研究所提出的發現可為Akt1基因缺損小鼠之性別差異提供其背後的分子機制，但仍須進一步的實驗去證實以及探索。

Schizophrenia is a severe mental disorder with complex genetic composition. Sex differences in schizophrenia are widely reported in the prevalence of disease, age of onset, symptoms, and responses to antipsychotics. However, the underlying molecular mechanism of the sex differences remain elusive, and a better understanding may provide new ways of treatment and/or insights to the disorder. Accumulating evidences from human genetic studies suggests that AKT1 (protein kinase B α), a key signaling kinase downstream of dopamine receptor D2 (DRD2), is associated with schizophrenia in several ethnic groups and it is one of the susceptibility genes which contribute to the pathogenesis of the disorder. Intriguingly, Akt1-deficient mice exhibited some characteristics of schizophrenia and sex differences were also reported in the Akt1-deficient mouse model, making it a suitable model to study not only schizophrenia but also its sex differences. In this thesis, behavior tests confirmed the sex differences of Akt1 heterozygous mutant mice (Akt1+/-), results showed higher reward sensitivity in male Akt1+/- mice (sucrose preference test) and higher sensitivity to methamphetamine in female mice (methamphetamine-induced behavioral sensitization). To further understand the molecular mechanism behind the sexual differences in Akt1+/- mice and their wild-type (WT) littermate controls, RNA-sequencing technique was used in this study. Transcriptomic expression of striatum tissues from male and female early adult mice were analyzed, due to previous reports of abnormal striatal DRD2 activity of Akt1+/- mice. Differential expression analysis revealed that Akt1-deficiency increased the sex differences of gene expression profile (WT♂vs. WT♀: 14 differentially expressed (DE) genes; Akt1+/-♂ vs. Akt1+/-♀: 322), and female mice displayed more DE genes than male mice when comparing to WT mice of each sex (WT♂vs. Akt1+/-♂: 18; WT♀vs. Akt1+/-♀: 119). Furthermore, there are 92 genes that display interaction effects of the two factors. Gene ontology and pathway analysis showed altered immune-related functions and cell-cell interaction in male mice, while mRNA regulations are more affected in female mice. Results of gene validation with RT-qPCR indicates possible altered transcriptional activity in Akt1+/- female mice (Hipk3, Ankrd10, Map4k5). Sex differences in dopamine-related genes may reveal the sex differences observed in behavioral evaluations (Prprn2, Tspan7). Genes related to Akt/Akt1 also demonstrated sex differences (Cadm2, Bmi1, Lnp). Genes and gene lists reported by this study could be candidates for the mechanism of sex differences behind Akt1-deficient mouse model of schizophrenia. Further experiments are needed to confirm the roles of each gene and test possible molecular actions.

1. Introduction pg. 1
1.1 Schizophrenia and Its Sex Differences pg. 1
1.2 Akt1-Deficeint Mouse Model as a Research Tool for Schizophrenia pg. 16
1.3 Application of RNA-Sequencing on Schizophrenia Research pg. 25
1.4 Objectives of This Thesis pg. 30
2. Materials and Method pg. 33
2.1 Animals pg. 33
2.2 Behavioral Evaluation pg. 33
2.3 RNA-Sequencing pg. 35
2.4 Reverse Transcription Real-Time Quantitative PCR (RT-qPCR) pg. 38
2.5 Statistical Analysis pg. 39
3. Results pg. 41
3.1 Behavioral Evaluation pg. 41
3.2 RNA-Sequencing pg. 46
3.3 Reverse Transcription Real-Time Quantitative PCR (RT-qPCR) pg. 54
4. Discussion pg. 61
4.1 Behavioral Evaluations Reveal Possible Sex Differences in The Dopaminergic Systems of Akt1+/- Male and Female Mice pg. 62
4.2 Akt Interaction with Estradiol Signaling Transduction Pathway Could Be a Possible Explanation to Increased Differential Gene Expression in The Striatum of Female Akt1+/- Mice Observed in RNA-Sequence Data pg. 68
4.3 Female Akt1+/- Mice Display Increased Expression of Genes Associated with Transcription Regulation pg. 72
4.4 Sex Difference in Expression of Genes Associated with DA-Related Functions May Reveal Possible Mechanism Behind the Sex Differences of Behaviors pg. 75
4.5 Genes Associated with Akt1 Display Sex Differences pg. 77
4.6 Principal Component Analysis Reveal Possible Outliers that Require Further Analysis pg. 79
4.7 Limitations, Future Directions and Conclusions pg. 82
5. References pg. 87
6. Figures and Tables pg. 123
7. Supplementary Figures and Tables pg. 149

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