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| 研究生： |
林万焜 Lin, Wan-Kun |
|---|---|
| 論文名稱： |
IFITM基因剔除鼠之下視丘功能之缺失研究 Study of hypothalamus dysfunctions in IfitmDel mutant mice |
| 指導教授： |
陳紹寬
Chen, Shau-Kawun |
| 口試委員: |
盧主欽
戴宗玄 |
| 學位類別： |
碩士
Master |
| 系所名稱： |
理學院 - 神經科學研究所 Graduate Institute of NeuroScience |
| 論文出版年： | 2017 |
| 畢業學年度： | 106 |
| 語文別： | 英文 |
| 論文頁數： | 113 |
| 中文關鍵詞： | IFITM基因剔除鼠 、下視丘發炎 、下視丘功能破壞 |
| 外文關鍵詞： | IfitmDel mice, Hypothalamic inflammation, Hypothalamic dysfunctions |
| 相關次數： | 點閱：22 下載：5 |
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Ifitm基因是一群可被干擾素刺激表現的基因，目前已知這些基因參與細胞對病毒的防禦，然而其生化特性及這些基因參與的其他生物功能並不清楚。將這些基因敲除後小鼠會產生過度攝食的行為並會造成肥胖，同時在下視丘中黑皮質素的前驅物POMC的表現量顯著降低，此發現表明破壞Ifitm基因可導致下視丘功能被破壞。然而由於代謝的調控並非只由下視丘控制，Ifitm基因是否直接參與下視丘的功能並不清楚。本研究卽是在探討Ifitm基因是否在下視丘的功能中扮演重要的角色。我們首先透過與下視丘功能有關的行為分析測試是否有其他下視丘功能被破壞的證據。我們發現在IFITM基因剔除公鼠，3-6個月開始出現過度攝食的行為與體重明顯增加；然而IFITM基因剔除母鼠在18個月後才出現同樣的表現型。IFITM基因剔除公鼠，在OFT與FST的行為測試中行動力下降，IFITM基因剔除母鼠卻有較多的活動；在公鼠與母鼠中焦慮均顯著增加。我們進一步測試這些剔除鼠的下視丘組織及神經胜肽的表現，在組織分析中並沒有發現組織結構異常。在神經胜肽的分析中IFITM基因剔除鼠的CRF的表現量增加，與IFITM基因剔除鼠的焦慮行為顯示相同趨勢。POMC表現的減少與CRF表現的上升顯示下視丘的功能紊亂。我們同時發現IFITM基因剔除鼠中微膠細胞數增加，以及位於下視丘的細胞本體的體積增加。另外IFITM基因剔除鼠中的細胞激素TNF-α與IL-1β在周邊血清中的增加表明此剔除鼠的下視丘產生發炎。本研究發現剔除IFITM基因會造成多項下視丘功能受到影響，並發現此突變鼠有下視丘發炎的現象。此下視丘發炎是否為下視丘功能破壞的主因，及IFITM基因剔除鼠的下視丘功能異常的細胞分子機制將會進一步被分析。
Ifitm genes are a group of interferon-inducible genes, best known for their antiviral roles. Their biological functions other than cellular antivirus and the biochemical properties of these proteins are not well-understand. Previously age-dependent hyperphagia and obesity were reported in IfitmDel mutant mice, in which 5 Ifitm genes were deleted. The levels of pro-opiomelanocortin (POMC) in hypothalamus of these mice were significantly reduced, suggesting that the hyperphagia phenotype of IfitmDel mutants is caused by defective central melanocortin signaling. In this study, we examine whether the hypothalamic dysfunctions are developed in these mutants. Whether hypothalamus associated behaviors are disrupted in IfitmDel mutants was first examined. We discovered that the hyperphagia and obesity phenotype in IfitmDel mutants are gender-dependent. These phenotypes in male mutants are detectable starting from 4-6 months of age, but not detected until one-year old in female mutants. Male mutants reveal the trends of decreased activities, while female mutants exhibit increased locomotor activity. Both gender develop anxiety-like phenotype. The behavioral abnormalities support the hypothesis of hypothalamic dysfunctions. As the Ifitm genes are expressed in various stage during development, the anatomy and the functions of the hypothalamus of these mutants were further tested. The histological analyses show no anatomical defects, neuron count differences and morphological alterations of neurons in IfitmDel mutant brains of both genders. These results indicate that these proteins are rather crucial for maintaining normal physiology in the developed central nervous system (CNS). The expression levels of neuropeptides related to stress response and anxiety or depression status, such as corticotrophin releasing factor (CRF), are altered in mutant hypothalamus. In contrast, Cell count and cell body size of microglia, whereas sera levels of pro-inflammatory cytokines, including TNF-α and IL-1β are elevated in IfitmDel mice, indicating hypothalamic inflammation and microglial activation phenotypes. The cellular mechanisms underlying the hypothalamic dysfunctions and the causative relationship of the hypothalamic inflammation with these phenotypes shall be further explored in the future studies.
中文摘要 I
Abstract II
Table of content IV
Abbreviation 1
Introduction 3
1 Interferon-inciduble-tsnsmembrance protein (IFITM) 3
1.1Type of IFITM protein and their roles 3
1.2 IFITM deletion mice phenotype link to Hyperphagia 6
1.3 Hyperphagia and eating disorder 7
1.3.1 Hypothalamus dysfunction and circuity 9
1.3.2 Regulation of feeding condition and its structure of Hypothalamus 11
1.3.3 Neuro circuity or endocrine regulation in hypothalamus of feeding behavior 13
1.4 Hypothalamus and associates differentially with animal behavior 14
1.4.1 The hypothalamus and limbic system related behavior 14
1.4.2 Anxiety disorders regulation by the hypothalamus 15
1.4.3 Motor control of the hypothalamus 16
1.5 Inflammation and obesity and metabolism disorder 17
1.5.1 Link inflammation state and hyperphagia to metabolism disorder 18
1.6 Rationale and experimental design in this study 18
Material and Methods 24
2.1 Mice 24
2.2 Open field test (OFT) 24
2.3 Elevated Plus Maze test (EPM) 25
2.4 Tail Suspension Test (TST) 25
2.5 Forced Swimming Test (FST) 26
2.6 Barnes maze test (BM) 26
2.7 Social interaction test 27
2.8 Immunohistochemistry 28
2.9 Nissl staining 29
2.10 ELISA (enzyme-linked immunosorbent assay) 30
2.11 RNA extraction from hypothalamus, Real time PCR 31
Result 33
3.1 Hyperphagia and weight gain in IfitmDel mice 33
Figure 1. Hyperphagia and weight gain only in young IfitmDel male mice (3-6months) and old mice (after16 month) of both gender in IfitmDel mice 36
3.2 IfitmDel mice exhibit higher locomotor activity in open field test (OFT) 38
Figure 2. IfitmDel mice exhibit higher locomotor activity in open field test (OFT) 40
3.3 IfitmDel mice reveal increased anxiety status in elevated plus maze (EPM) 41
Figure 3. IfitmDel mice reveal increased anxiety status in elevated plus maze (EPM) 43
3.4 Male mice spent more immobility time in depression-like behavior test 44
Figure 4. Male mice spent more immobility time in depression-like behavior test 45
3.5 Lower activity in first trail in learning and memory test of male mice on Barnes Maze test (BM) 46
Figure 5. Lower activity in first trail in learning and memory BM test 48
3.6 No Differences in Social Behavior of IfitmDel mice 49
Figure 6 No Differences in Social Behavior of IfitmDel mice 50
3.7 Histological and immunohistochemical analysis of brain in IfitmDel mice 51
Figure 7. Histological analysis of brain defects in IfitmDel mice 56
Coronal section form cerebrum to cerebellum 56
3.8 TH (Tyrosine hydroxylase) cell showed no difference in IfitmDel mice 56
Figure 8. The production of the enzyme tyrosine hydroxylase (TH) 58
Cell showed no different in IfitmDel mice. 58
3.9 QPCR (Quantitative real-time PCR validation) results measuring neuropeptide levels in IfitmDel mice. 58
Figure 9 QPCR (Quantitative real-time PCR validation) result in IfitmDel mice 59
3.10 The activation status of microglia are changed in cortex, hypothalamus 60
Figure 10. Increase in cortex and Basal ganglia of microglia numbers, cell body size in the hypothalamus 64
3.11 Astrocyte showed no obvious different 64
Figure 11. Astrocyte show no obvious different in IfitmDel mice 66
3.12 inflammation 67
Figure 12. Inflammation in periphery plasma cell and brain 69
Summary of our findings 70
Discussion 72
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