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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李立仁 | zh_TW |
| dc.contributor.advisor | Li-Jen Lee | en |
| dc.contributor.author | 呂宜臻 | zh_TW |
| dc.contributor.author | Yi-Chen Lu | en |
| dc.date.accessioned | 2026-03-13T16:46:04Z | - |
| dc.date.available | 2026-03-14 | - |
| dc.date.copyright | 2026-03-13 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-10-14 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102142 | - |
| dc.description.abstract | 充足睡眠對大腦發育至關重要。青少年時期的睡眠不足會對神經發育產生深遠影響，並可能增加罹患精神疾病(如思覺失調症)的風險。為探討此問題，我們使用異型合子Disc1突變(heterozygous, Het)與野生型(wild-type, WT)小鼠，在兩種睡眠干擾條件下進行實驗：72 小時睡眠剝奪(sleep deprivation, SD)及 3 週長期睡眠限制(sleep restriction, SR)，並採用兩種干擾方式：多平台(multi-platform, MP)與掃動桿(sliding bar, SB)。我們重點檢測了與精神分裂症相關的特徵，包括海馬體神經新生(hippocampal neurogenesis)、微膠細胞(microglia)、樹突形態(dendritic morphology以及棘突發育(dendritic spine development)。
在72小時睡眠剝奪的模式之下，Ki67免疫染色顯示，神經新生的增殖(proliferation)僅在SD-MP下受到影響：WT小鼠下降，而Het小鼠則顯著增加，呈現基因型差異性反應。相比之下，SD-SB 對增殖無明顯影響。DCX標記的神經成熟(maturation)結果顯示，Het小鼠在基線水平即高於WT小鼠。在WT小鼠，兩種SD模式均導致DCX細胞增加，而在Het小鼠腦中，SD-MP造成DCX細胞下降。檢測Iba1標記的微膠細胞，結果顯示區域與基因型特異性差異：WT小鼠在SD-SB條件下，微膠細胞密度在齒狀迴(dentate gyrus)顆粒細胞層(granule cell layer)有輕度上升，而Het小鼠在SD-MP條件下，微膠細胞密度則在顆粒下區(subgranular zone)出現顯著增加。 為模擬青少年睡眠不足，我們建立青少年(P28)小鼠長期睡眠限制模。小鼠被限制為每天僅睡6小時，每週5天，持續3週。Ki67結果顯示，在SR-MP下，神經新生的增殖在兩種基因型小鼠中均下降，而SR-SB則無影響。DCX結果顯示，WT小鼠不受影響，但Het小鼠在MP與SB條件下均有顯著增加，提示對睡眠限制的敏感性更高。微膠細胞在 SR-SB 條件下於分子層(molecular layer)與顆粒細胞層增加，而在顆粒下區減少；SR-MP 對微膠細胞無顯著影響。 在青少年早期(P28)，齒狀迴顆粒細胞的樹突形態，在WT與Het小鼠中無明顯差異。經過3週後，WT組樹突結構保持穩定，且不受睡眠條件影響。然而，Het組的樹突在SR-SB條件下顯示，分支點(nodes)、末端(ends)與段(segments)數顯著增加，顯示分支異常。Sholl 分析顯示，隨年齡增長，兩種基因型的近端樹突複雜度自然下降，但SR-SB使Het小鼠的細胞保持較高複雜度。正常情況下段長(segment length)隨年齡增加，但在Het-SB組，此增長受阻。 我們也比較了WT與Het小鼠齒狀迴顆粒細胞的樹突棘密度與形態。在青少年早期(P28)，兩種小鼠在棘突密度尚無差異，但Het組在遠端樹突(distal dendrites)上未成熟棘較少、成熟棘較多。經3週後，WT小鼠在SR-MP下樹突棘密度下降，而Het小鼠在經歷SR-MP與SR-SB後，樹突棘密度均顯著增加。樹突棘的形態上，WT與Het小鼠在SR-SB條件下樹棘突的成熟化均下降。在青少年階段，樹棘突通常會轉變為成熟型態，SB會阻止其發育進展。 睡眠干擾會影響海馬體神經新生、微膠細胞密度、樹突分支以及棘突發育。Disc1的缺損與干擾的方法有不同的效果。這些結果提示，遺傳易感性與睡眠不足相互作用，可能影響神經發育並增加精神分裂症的風險。 | zh_TW |
| dc.description.abstract | Adequate sleep is essential for brain development, and insufficient sleep during adolescence profoundly impacts neurodevelopment, increasing the risk of psychiatric disorders such as schizophrenia. To investigate this, we used Disrupted in schizophrenia 1 (Disc1) heterozygous mutant (Het) and wild-type (WT) mice under two paradigms of sleep interference: 72-hour sleep deprivation (SD) and chronic 3-week sleep restriction (SR), implemented by either the multi-platform (MP) or sliding bar (SB) method. We examined hippocampal neurogenesis, microglia, dendritic morphology, and dendritic spine development across adolescence and early adulthood.
In the 72-hour SD paradigm, Ki67 staining revealed that proliferation was altered only under SD-MP: WT mice showed reduced proliferation, whereas Het mice showed an increase, reflecting genotype-dependent effects. Neuronal maturation, assessed by DCX, was higher in Het mice at baseline. SD increased DCX-positive cells in WT under both MP and SB, while Het mice showed a decrease only under MP. Microglial density (Iba1 staining) exhibited region- and genotype-specific changes: WT mice under SB showed modest increases in the granule cell layer, whereas Het mice under MP displayed increased microglia in the subgranular zone. To simulate the adolescent sleep insufficient condition, we developed a 3-week SR model (P28–P50, 6 h/day sleep, 5 days/week). Proliferation of DG neurons decreased under SR-MP in both genotypes, while SR-SB had no effect. For maturation, WT mice were unaffected, but Het mice exhibited robust increases in DCX-positive cells under both MP and SB. Microglial density increased in the molecular and granule cell layers under SR-SB in both genotypes, but decreased in the subgranular zone; SR-MP produced no microglial changes. At baseline (P28), dendritic morphology did not differ between genotypes. After three weeks, the dendritic structure remained stable in WT, regardless of sleep condition. However, Het mice under SR-SB displayed significant increases in dendritic nodes, ends, and segments, indicating abnormal branching. Sholl analysis revealed natural reductions in proximal dendritic complexity with age in both genotypes, but this decline was prevented in Het mice under SR-SB. Normally, segment length increased with age, but this was blunted in Het mice under SR-SB. At P28, spine density was comparable between genotypes, though Het mice showed fewer immature and more mature spines in distal dendrites. After three weeks, WT spine density decreased only under SR-MP, whereas Het mice exhibited increased density under both SR-MP and SR-SB. Morphological analysis revealed that WT spines shifted toward immaturity after SR, particularly under SB. Het mice, which already had a higher proportion of immature spines under normal sleep, showed further increases after both forms of SR. Developmentally, WT mice transitioned toward more mature spines, whereas Het mice failed to do so, with SR-SB preventing normal maturation. Overall, sleep interference altered hippocampal neurogenesis, microglial density, dendritic branching, and spine development in both a genotype- and method-dependent manner. These findings suggest that genetic vulnerability interacts with sleep disruption to impair neurodevelopmental trajectories relevant to schizophrenia. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-03-13T16:46:04Z No. of bitstreams: 0 | en |
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| dc.description.tableofcontents | 口試委員會審定書 I
致謝 II 中文摘要 III ABSTRACT V CHAPTER 1. INTRODUCTION 1 CHAPTER 2. MATERIALS AND METHODS 8 2.1 ANIMALS 8 2.2 SLEEP EXPERIMENTAL DESIGN 8 Multi-platform (MP) 8 Automatic sliding bar (SB) 9 72-hour sleep deprivation (SD) 9 3-week sleep restriction (SR) 9 2.3 HISTOLOGICAL EXAMINATION 10 Perfusion 10 Immunohistochemistry 10 Golgi stain 11 Reconstruction and morphometric analyses of granular cells and microglia 11 Dendritic spine density and morphology analyses. 11 2.4 STATISTICAL ANALYSIS 12 CHAPTER 3. RESULTS 13 3.1 SEVENTY-TWO-HOUR SLEEP DEPRIVATION ALTERS HIPPOCAMPAL NEUROGENESIS AND MICROGLIA IN YOUNG ADULT MICE. 13 3.2 THREE-WEEK SLEEP RESTRICTION ALTERS HIPPOCAMPAL NEUROGENESIS IN ADOLESCENT MICE. 15 3.3 DENDRITIC STRUCTURE AND COMPLEXITY IN ADOLESCENT MICE BEFORE AND AFTER SLEEP RESTRICTION 18 3.4 DEVELOPMENTAL CHANGES IN DENDRITIC STRUCTURE AND THE IMPACT OF SLEEP RESTRICTION 20 3.5 ALTERATIONS IN DENDRITIC SPINE DENSITY AND MORPHOLOGY CLASSIFICATION AT P28 MICE 22 3.6 CHANGES IN SPINE DENSITY AND SUBTYPE-SPECIFIC SPINE MORPHOLOGY FOLLOWING SLEEP RESTRICTION 23 3.7 CHANGES IN SPINE DENSITY AND SUBTYPE-SPECIFIC MORPHOLOGY ACROSS ADOLESCENCE IN WT AND HET MICE 24 CHAPTER 4. DISCUSSION 27 4.1 GENOTYPE-DEPENDENT NEUROGENESIS CHANGES UNDER MULTIPLE PLATFORM SLEEP RESTRICTION 27 4.2 DIFFERENTIAL MICROGLIAL RESPONSES TO SLEEP INTERFERENCE 29 4.3 DENDRITIC AND SPINE ALTERATIONS IN DISC1 HETEROZYGOUS MICE UNDER SLEEP RESTRICTION 30 4.4 CELLULAR AND CLINICAL INSIGHTS ON GENETIC RISK AND SLEEP RESTRICTION IN SCHIZOPHRENIA 31 4.5 CONCLUSION 33 CHAPTER 5. FIGURES AND TABLES 35 FIGURE 1. METHODS FOR SLEEP INTERFERENCE. 35 FIGURE 2. THE EXPERIMENTAL DESIGN 1. 36 FIGURE 3. PROLIFERATIVE FEATURE IN THE HIPPOCAMPAL DENTATE GYRUS IN YOUNG ADULT MICE WITH OR WITHOUT 72-HOUR SLEEP DEPRIVATION. 37 FIGURE 4. EFFECTS OF 72-HOUR SLEEP DEPRIVATION ON THE DENSITY OF MATURING NEURONS IN THE HIPPOCAMPAL DENTATE GYRUS. 38 FIGURE 5. MICROGLIAL RESPONSE TO 72-HOUR SLEEP DEPRIVATION. 39 FIGURE 6. THE EXPERIMENTAL DESIGN 2. 40 FIGURE 7. PROLIFERATIVE CELLS IN THE HIPPOCAMPAL DENTATE GYRUS IN ADOLESCENT MICE WITH OR WITHOUT 3-WEEK SLEEP RESTRICTION. 41 FIGURE 8. EFFECTS OF 3-WEEK SLEEP RESTRICTION ON THE DENSITY OF MATURING NEURONS IN THE HIPPOCAMPAL DENTATE GYRUS. 42 FIGURE 9. CHANGES IN MICROGLIA DENSITY IN THE DENTATE GYRUS FOLLOWING THREE WEEKS OF SLEEP RESTRICTION. 43 FIGURE 10. MORPHOMETRIC ANALYSIS OF DG NEURONS IN P28 MICE. 44 FIGURE 11. DENDRITIC COMPLEXITY OF DG GRANULE CELLS IN P28 MICE. 45 FIGURE 12. ANALYSIS OF NEURONAL DENDRITIC BRANCHED STRUCTURE. 46 FIGURE 13. THE MORPHOMETRIC ANALYSIS EVALUATED DENDRITIC COMPLEXITY AFTER 3-WEEK SLEEP RESTRICTION. 47 FIGURE 14. DEVELOPMENTAL CHANGES IN DENDRITIC FEATURES BETWEEN P28 AND P50. 48 FIGURE 15. DENDRITIC COMPLEXITY BETWEEN P28 AND P50. 49 FIGURE 16. DENDRITIC DEVELOPMENT WITH AND WITHOUT SLEEP RESTRICTION. 50 FIGURE 17. SPINE DENSITY IN THE DG GRANULE CELLS AT P28. 51 FIGURE 18. MORPHOLOGICAL CLASSIFICATION OF DENDRITIC SPINES IN P28 MICE. 52 FIGURE 19. SPINE DENSITY IN THE GRANULE CELLS AFTER 3-WEEK SLEEP RESTRICTION IN ADOLESCENT MICE. 53 FIGURE 20. MORPHOLOGICAL CLASSIFICATION OF DENDRITIC SPINES AFTER 3-WEEK SLEEP RESTRICTION IN ADOLESCENT MICE. 54 FIGURE 21. EFFECTS OF DEVELOPMENT AND ADOLESCENT SLEEP RESTRICTION ON THE DENDRITIC SPINE DENSITY BETWEEN GENOTYPES. 55 FIGURE 22. DEVELOPMENTAL CHANGES OF DENDRITIC SPINES. 56 TABLE 1. ANTIBODIES USED IN THE PRESENT STUDY. 57 TABLE 2. EFFECTS OF DIFFERENT SLEEP INTERFERENCE METHODS ON HIPPOCAMPAL NEUROGENESIS. 58 TABLE 3. EFFECTS OF DIFFERENT SR METHODS ON MICROGLIA DENSITY IN THE DG SUBREGIONS. 59 TABLE 4. EFFECTS OF DIFFERENT SR METHODS ON THE DEVELOPMENT OF DG NEURON DENDRITE MORPHOLOGY. 60 TABLE 5. EFFECTS OF DIFFERENT SR METHODS ON THE DEVELOPMENT OF DG NEURON SPINE MORPHOLOGY. 61 REFERENCES 62 | - |
| dc.language.iso | en | - |
| dc.subject | 睡眠剝奪 | - |
| dc.subject | 睡眠限制 | - |
| dc.subject | 青少年 | - |
| dc.subject | 神經新生 | - |
| dc.subject | 微膠細胞 | - |
| dc.subject | 樹突形態 | - |
| dc.subject | 樹突棘 | - |
| dc.subject | 思覺失調症 | - |
| dc.subject | Sleep deprivation | - |
| dc.subject | Sleep restriction | - |
| dc.subject | Adolescence | - |
| dc.subject | Neurogenesis | - |
| dc.subject | Microglia | - |
| dc.subject | Dendritic morphology | - |
| dc.subject | Dendritic spines | - |
| dc.subject | Schizophrenia | - |
| dc.title | 論睡眠不足對Disc1基因缺損小鼠海馬迴神經組織的影響 | zh_TW |
| dc.title | Impact of sleep insufficiency on hippocampal neural tissue in heterozygous Disc1 mutant mice | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 段立珩;顏怡君;李彥霆 | zh_TW |
| dc.contributor.oralexamcommittee | Li-Heng Tuan;Yi-Chun Yen;Yen-Ting Li | en |
| dc.subject.keyword | 睡眠剝奪,睡眠限制青少年神經新生微膠細胞樹突形態樹突棘思覺失調症 | zh_TW |
| dc.subject.keyword | Sleep deprivation,Sleep restrictionAdolescenceNeurogenesisMicrogliaDendritic morphologyDendritic spinesSchizophrenia | en |
| dc.relation.page | 69 | - |
| dc.identifier.doi | 10.6342/NTU202504565 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-10-16 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
| dc.date.embargo-lift | 2028-09-09 | - |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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