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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 賴文崧 | zh_TW |
| dc.contributor.advisor | Wen-Sung Lai | en |
| dc.contributor.author | 裴如淳 | zh_TW |
| dc.contributor.author | Ju-Chun Pei | en |
| dc.date.accessioned | 2024-03-05T16:17:16Z | - |
| dc.date.available | 2024-03-06 | - |
| dc.date.copyright | 2024-03-05 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-02-04 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92100 | - |
| dc.description.abstract | 認知缺損為思覺失調症重要的臨床症狀，但現行治療效果不彰，可能來自於我們對病患的認知缺損了解不夠徹底。過去研究指出病患在涉及執行功能與酬賞學習的決策作業上有所缺損。此外，近來許多研究指出AKT1這個思覺失調症之候選基因和認知缺損高相關，可能由於其涉及神經傳導物和神經活動異常導致。但，AKT1基因缺損和GABA神經傳導物系統異常是否和思覺失調症認知缺損有關，仍是未解之謎。故，本研究目標即為了解AKT1是否影響相關腦區神經活動，或特定GABA神經元亞型表現量，並進一步導致酬賞型決策作業缺損。首先，使用AKT1缺損小鼠發現其異常行為表現，及在背內側紋狀體發現神經活動異常。又，觀察到其在背內側紋狀體中，GABA神經元亞型: parvalbumin的表現量下降。所以我們再進一步使用一般小鼠，使其Akt1在背內側紋狀體表現量下降，發現行為異常模式與AKT1缺損小鼠缺損老鼠很相似。最後，我們操弄Akt1在parvalbumin神經元之表現，發現Akt1此特定神經元表現下降，亦會產生相似之缺損。這顯示，AKT1之缺損主要影響到背內側紋狀體parvalbumin神經元之表現量，造成神經活動異常，進一步導致酬賞學習決策作業表現異常。 | zh_TW |
| dc.description.abstract | The treatment of cognitive impairment in patients with schizophrenia is of great importance due to unmet medical needs. Previous research has shown that schizophrenia affects reward-based decision making, which are related to executive functions and motivation/reinforcement learning. Increasing evidence implicates the involvement of AKT1, a schizophrenia candidate gene, in cognitive impairment of schizophrenia, which involves neuromodulation and neuronal connectivity. However, the impact of AKT1 deficiency on GABAergic neurons has been less explored so far. It is of great interest to investigate the importance of AKT1 on GABAergic neuron subtypes, especially in reward-based decision making. Thus, taking advantage of Akt1 heterozygous mutant mice (Akt1+/-) as a mouse model of schizophrenia, our study aimed to investigate the involvement of Akt1 in GABAergic neuron function and its impact on brain activity in relevant brain regions in a probabilistic decision-making task. First, Akt1+/- mice exhibited a distinct behavioral pattern during the task, and an altered neural activity in DMS. Then, Akt1+/- mice exhibited a region-specific reduction of PV, and a selective decrease of Akt1 was also found in PV neurons. Furthermore, DMS-specific knockdown Akt1 mice reproduced the alterations in Akt1+/- mice. Finally, we found that mice with conditional Akt1 knockout in parvalbumin (PV), not in GABAergic neuron (GAD), recapitulated behavioral alterations in Akt1+/- mice. Akt1+/- mice, DMS-specific knockdown Akt1 mice, and conditional knockout mice of Akt1 in PV neurons all showed an increase in the lose-stay rate for high reward choice and no-reward learning. Furthermore, all mice demonstrated a decrease in choice consistency. These findings suggest that Akt1 affects PV neurons, particularly in DMS, potentially influencing distinct cognitive processes. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-03-05T16:17:16Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-03-05T16:17:16Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii Table of contents v List of Tables and Figures ix Chapter 1 Introduction 1 1.1. Overview of schizophrenia 1 1.1.1. What is schizophrenia 1 1.1.2. Cognitive dysfunction in schizophrenia 3 1.1.3. The GABA hypothesis of schizophrenia 5 1.1.4. The etiology of schizophrenia 7 1.2. Overview of reward-based decision making 10 1.2.1. The clinical application 11 1.2.2. The related brain regions 13 1.2.3. Computational analysis model 18 1.3. What is AKT1? 22 1.3.1. The association between AKT1 and cognitive impairment in schizophrenia 22 1.3.2. Cell signaling of AKT1 24 1.3.3. AKT1 is involved in several neurotransmitter pathways, especially in the GABAergic system 25 1.4. Using animal models of schizophrenia to study the reward-based decision-making process 26 1.4.1. Taking advantage of genetic manipulation 27 1.4.2. Akt1 mutant mice are ideal for mimicking schizophrenia-like cognitive functions 28 1.4.3. The alteration of GABAergic system in Akt1-/- mice 29 1.5. The objective of this study 30 Chapter 2 Methods 33 2.1. Animals 33 2.2. Food restriction schedule 35 2.3. Open field task 35 2.4. Dynamic foraging task 36 2.5. Surgery 49 2.6. LFP recording and power spectral density analysis 50 2.7. Immunofluorescent staining 51 2.8. Virus injection 52 2.9. Statistics 53 Chapter 3 Results 55 Exp. 1: The neuronal activity within related brain regions during dynamic foraging task in Akt1+/- mice 55 Exp. 2: The expression pattern of Akt1 and PV of Akt1+/- mice in related brain regions. 61 Exp. 3: The effect of specific knockdown Akt1 on DMS. 63 Exp. 4.1 The role of Akt1 on GABAergic neurons in the dynamic foraging task 67 Exp. 4.2 The role of Akt1 on parvalbumin neurons in the dynamic foraging task 71 Chapter 4 Discussion 77 4.1 Summary of this study 77 4.2 Akt1 deficiency modulated choice strategy, reward learning rate and choice consistency in reward learning 78 4.3 The effect of Akt1 on DMS plays a crucial role in the dynamic foraging task 81 4.4 Akt1 deficiency has a distinct impact on PV neurons. 84 4.5 Limitations and future plan 90 Figures and Tables 95 Supplementary 137 | - |
| dc.language.iso | en | - |
| dc.title | 探索思覺失調症候選基因AKT1影響GABA神經元亞型在酬賞型決策作業扮演之角色 | zh_TW |
| dc.title | Investigate the role of AKT1, a schizophrenia candidate gene, on GABAergic neuron subtypes in reward-based decision making task in male mice | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 林士傑;姚皓傑;張芳嘉;張鈞惠;蕭逸澤 | zh_TW |
| dc.contributor.oralexamcommittee | Shi-Chieh Lin;Hau-Jie Yao;Fang-Chia Chang;Chun-Hui Chang;Yi-Tse Hsiao | en |
| dc.subject.keyword | 思覺失調症,認知缺損,酬賞學習決策作業,酬賞學習模型,背內側紋狀體, | zh_TW |
| dc.subject.keyword | schizophrenia,Akt1 mice,probabilistic learning task,reinforcement learning model,parvalbumin (PV),dorsal medial striatum (DMS), | en |
| dc.relation.page | 177 | - |
| dc.identifier.doi | 10.6342/NTU202400437 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-02-06 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 心理學系 | - |
| Appears in Collections: | 心理學系 | |
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