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標題: | 以思覺失調症小鼠為模式探討聚胞苷酸誘導母體免疫激活和絲氨酸消旋酶缺損間可能的交互作用 Investigation of possible epistatic interactions between poly(I:C)-induced maternal immune activation and serine racemase mutations in mouse model of schizophrenia |
作者: | 陳圓圓 Yuan-Yuan Chen |
指導教授: | 賴文崧 Wen-Sung Lai |
關鍵字: | 思覺失調症,絲氨酸消旋酶,聚肌胞苷酸,產前免疫活化,小鼠模式,雙重打擊假說, schizophrenia,serine racemase,poly(I:C),maternal immune activation,mouse model,two-hit hypothesis, |
出版年 : | 2023 |
學位: | 碩士 |
摘要: | 思覺失調症為一種嚴重的心理疾患,且影響全球約1%的人口,但其致病機轉至今仍尚未被透徹瞭解。過往研究已指出有多種因素可能共同導致思覺失調症,包括遺傳因子和環境因子等等。而思覺失調症的雙重打擊假說提出,遺傳缺損結合早期發展中的環境刺激,最終可能導致思覺失調症發病。在這個前提之下,我們的研究欲以小鼠為模式探討思覺失調症其中之一候選基因─絲氨酸消旋酶(SR)缺損以及產前聚肌胞苷酸(poly(I:C))所導致免疫活化引起的胎兒感染之間可能存在的交互作用。我們的研究共包括了三個實驗,實驗組為SR雜合子孕鼠在懷孕的第17.5天注射一劑聚肌胞苷酸(5mg/kg)之子代,對照組則是予以生理食鹽水。在實驗1中我們發現不論基因型在聚肌胞苷酸注射6小時過後,小鼠胚胎全腦中的三種促炎性細胞因子(IL-6,IL-1β和TNF-α)之蛋白質水平皆有升高。在實驗2中,則是以胚胎時期接受過聚肌胞苷酸或生理食鹽水介入的SR新生小鼠(實驗2.1)和成鼠(實驗2.2)執行一系列的行為測試。在新生期所進行的一組行為測驗包括翻身反射 (P3-7),地性反射(P3-7),抓握反射(P5-7)和開闊場測試(P26)。產前接觸聚肌胞苷酸導致其神經運動功能的發展延遲,特別是在SR同合子新生小鼠。在成年期,相同的小鼠群體被測試以評估其負性和認知功能。我們在成鼠(P80及以上)進行了另一組行為測驗,包括開闊場測試、自發交替探索實驗、新物件辨識測驗、注意力測試、社交測試和痕跡恐懼制約測試。而聚肌胞苷酸影響了特定基因型的SR小鼠,明顯導致其運動活動、長期記憶和情境恐懼記憶的缺失。在實驗3中,我們測試另一個群體的新生期小鼠,以了解一種新型D-氨基酸氧化酶抑制劑(RS-D7)可能的拯救效果。而我們的結果發現,不論基因型,RS-D7有可能改善由聚肌胞苷酸引起的發展延遲。本研究試圖釐清思覺失調症病程中遺傳因素和環境因素複雜的交互作用,提供了有關產前免疫活化和SR基因突變在其中扮演腳色的重要發現。而造成這些行為差異背後的神經機轉仍需更進一步實驗研究生化層次的腦部變化才能更加了解。 Schizophrenia is a serious mental disorder that is affecting about 1% of the global population, but its pathophysiology is unknown. Previous studies have identified multiple factors, including genetic and environmental, that make contribution to the pathology of schizophrenia. The two-hit hypothesis of schizophrenia posits that schizophrenic symptoms are caused by a genetic susceptibility as well as early developmental injury. In this context, our study investigates potential epistatic interactions between mutations in the serine racemase (SR) gene, a candidate gene for schizophrenia, and prenatal polyinosinic acid-polycytidylic acid (poly(I:C))-induced immune activation, i.e., gestational infections during early development, using mice as a model. SR heterozygous pregnant dams received either a single injection of poly(I:C) (5 mg/kg) or a vehicle on gestation day 17.5, and three experiments were included. In Exp.1, our results revealed that protein levels of three pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) were elevated in fetal brains 6 hours after poly(I:C) injection, regardless of genotypes. In Exp.2, a battery of behavioral tests was conducted on poly(I:C)- or saline-treated SR offspring in neonates (Exp.2.1) and adulthood (Exp.2.2). During the neonatal period, a set of behavioral tests, including righting reflex (P3-7), geotaxis reflex (P3-7), grasping reflex (P5-7), and open field task (P26), was conducted. Prenatal poly(I:C) exposure led to developmental delays in neuromotor functions, particularly in SR HOM mice during the neonatal period. In adulthood, the same cohort of mice was tested to assess their negative and cognitive functions. Another set of behavioral tests was carried out in adult mice (P80 upwards), including the open field test, spontaneous alternation test, novel object recognition test, object-based attention test, 3-chamber social test, and trace fear conditioning test. In adulthood, poly(I:C) challenges notably affect locomotor activity, long-term memory, and contextual fear memory in adult SR mice of specific genotypes, respectively. A separate cohort of poly(I:C)- or saline-treated SR neonates was evaluated to understand the potential rescue effect of a novel D-amino acid oxidase inhibitor (RS-D7) in Exp. 3. Our findings indicated that RS-D7 had the potential to ameliorate developmental delays induced by poly(I:C) exposure, irrespective of genotypes. This study shed light on the intricate interplay of genetic and environmental factors in schizophrenia, offering valuable insights into the role of prenatal immune challenges and SR mutations. To further examine neural mechanisms underlying behavioral alterations, brain alterations at the biochemical level deserved further study. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91870 |
DOI: | 10.6342/NTU202304492 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 腦與心智科學研究所 |
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