評估精神分裂症動物模式之Akt1基因缺損小鼠在五擇一序列反應時程作業的注意力功能

Evaluation of Attentive Functions in Akt1 Mouse Model of Schizophrenia: Using the Five-Choice Serial Reaction Time Task (5-CSRTT)

陳雅珊(Ya-Shan Chen)

指導教授 ： 賴文崧

國立臺灣大學/理學院/心理學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.02909

摘要

精神分裂症是一種嚴重且多因子的精神疾患，並且具有高度的遺傳性。從人類遺傳學以及動物研究中，有愈來愈多的結果顯示AKT1基因可能參與了精神分裂症的致病歷程。在眾多精神分裂的臨床症狀上，精神分裂症患者具有明顯的認知功能異常，特別是注意力功能的缺損。連續操作測驗(continuous performance test)是常用於測量精神分裂症患者注意力功能的測驗，無論是精神分裂症患者或是與其有高血緣關係的親屬，普遍可觀察到他們在這測驗中具有較差的注意力表現。在動物研究中，五擇一序列反應時程作業(five-choice serial reaction time task)是個類似連續操作測驗的注意力作業，近年來廣泛用於評估大鼠或是小鼠的注意力表現。相較於針對人類所進行精神疾病遺傳連鎖研究的侷限性，基因突變小鼠的模式更能直接探究精神分裂症候選基因（如Akt1基因）的生物功能以及它在精神分裂症致病上之因果關係。本論文旨在探討AKT1是否參與精神分裂症的注意力功能，以Akt1基因缺損小鼠為模式，觀察牠們在五擇一序列反應時程作業中，是否表現與精神分裂症類似的注意力功能缺失。實驗採用的Akt1同型合子、異型合子與野生控制組之雄性小鼠，皆在改良式五擇一序列反應時程作業的儀器中進行注意力表現的評估。實驗程序可以概分成學習階段與測驗階段，小鼠接受一系列每日的訓練學習階段，直到連續三天在刺激燈亮2秒的情況下，達到大於80 %準確率、小於20 %遺漏率的基本學習標準，接著才能進入測驗階段。測驗階段包含四種需要更多注意力功能的測驗：降低刺激燈亮時間、改變等待刺激燈亮時間、增加刺激燈的亮度、以及加入聲音的干擾。實驗結果顯示，Akt1同型合子之小鼠在學習的第一階段持續地表現出較高的遺漏率。當給予足夠的訓練達到基本的學習標準後，Akt1基因缺損小鼠則與野生控制組小鼠皆具有相同的行為表現。在測驗階段的四個測試中，只有在增加刺激燈之亮度與聲音干擾的測驗中，Akt1基因缺損小鼠表現出不一致的衝動行為。本論文結果顯示Akt1基因缺損會影響小鼠注意力功能的表現，特別是學習的初期以及需要更多注意力投注的作業中。由此可以推測在病人身上AKT1的缺損會造成與精神分裂症相關之注意力功能的異常，進而影響其他認知功能的表現。

關鍵字

精神分裂症 ； Akt1 ； 注意力 ； 連續操作測驗 ； 五擇一序列反應時程作業

並列摘要

Schizophrenia is a severe and multifactor psychiatric disorder with a strong genetic component, and accumulating evidence from human genetics and animal studies suggest that AKT1 gene might play a role in the pathogenesis of schizophrenia. Schizophrenia contains heterogeneous clinical symptoms marked by significant cognitive impairments especially attentive dysfunction. Attention deficits measured by the continuous performance test (CPT), the most popular clinical-based measure in schizophrenia research, is commonly observed among schizophrenia patients and those at genetic risk for the disease. The five-choice serial reaction time task (5-CSRTT) has been considered to analogue to the CPT and increasingly used to assess attentive functions in rats and mice. As a mutant mouse model is a simple and relatively straightforward approach for determining the causal relationships and biological functions of AKT1 in schizophrenia, this thesis aims to discover the involvement of AKT1 in attetional functions of schizophrenia through investigating whether Akt1deficiency in mice results in attentive impairments by using the 5-CSRTT. In this study, male Akt1 homozygous (HOM) and heterozygous (HET) mutant mice and their wild-type (WT) littermates were tested in a modified version of the 5-CSRTT. Mice were trained in a sequence of daily learning sessions until they reached the baseline criteria with ≥ 80% accuracy and ≤ 20% omissions in the condition with 2-sec stimulus durations for three consecutive days. After reaching these criteria, each subject went over a sequence of four test conditions, which required more attentive load, including manipulations of stimulus duration, inter-trial-interval, stimulus brightness, and white noise distractors. Behavioral analysis indicated that Akt1 HOM mice have abnormal attention in the initially learning stage of the 5-CSRTT. After reaching preset criteria, Akt1-mutant mice showed normal baseline performances to enter those following tests. Both tests of brightness and white noise distractor inconsistently induced impulsive behavior instead of attention-related responses in Akt1-mutant mice. Our findings suggest that AKT1 may participate in attentive functions of schizophrenia.

並列關鍵字

schizophrenia ； Akt1 ； attention ； continuous performance test ； five-choice serial reaction time task

參考文獻

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