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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 王培育(Pei-Yu Wang) | |
dc.contributor.author | Ling-Ling Teng | en |
dc.contributor.author | 鄧翎翎 | zh_TW |
dc.date.accessioned | 2021-06-17T01:41:54Z | - |
dc.date.available | 2022-09-08 | |
dc.date.copyright | 2017-09-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-28 | |
dc.identifier.citation | Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell metabolism, 11(1), 35-46.
Braeckman, B. P., Demetrius, L., & Vanfleteren, J. R. (2006). The dietary restriction effect in C. elegans and humans: is the worm a one-millimeter human. Biogerontology, 7(3), 127-133. Bronson, R. T., & Lipman, R. D. (1990). Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice. Growth, development, and aging: GDA, 55(3), 169-184. Bruce‐Keller, A. J., Umberger, G., McFall, R., & Mattson, M. P. (1999). Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Annals of neurology, 45(1), 8-15. Burger, J., Buechel, S. D., & Kawecki, T. J. (2010). Dietary restriction affects lifespan but not cognitive aging in Drosophila melanogaster. Aging Cell, 9(3), 327-335. Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., ... & Auwerx, J. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 458(7241), 1056-1060. Cantó, C., & Auwerx, J. (2010). AMP-activated protein kinase and its downstream transcriptional pathways. Cellular and Molecular Life Sciences, 67(20), 3407-3423. Cire. Aging, National Institute on (2016-03-28). 'World’s older population grows dramatically'. National Institute on Aging. Retrieved 2017-05-01. Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., ... & Weindruch, R. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 325(5937), 201-204. Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nature communications, 5. Dawson, L. A., Nguyen, H. Q., & Li, P. (2001). The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology, 25(5), 662-8. Duan, W., & Mattson, M. P. (1999). Dietary restriction and 2‐deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. Journal of neuroscience research, 57(2), 195-206. Duhr, F., Déléris, P., Raynaud, F., Séveno, M., Morisset-Lopez, S., La Cour, C. M., ... & Chaumont-Dubel, S. (2014). Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nature chemical biology, 10(7), 590-597. Finch, C. E., & Roth, G. S. (1999). Biochemistry of aging. Basic neurochemistry, molecular, cellular and medical aspects (Eds. GJ Siegel, BW Agranoff, RW Albers, SK Fisher and MD Uhler). Lippincott-Raven Publishers, Philadelphia, 613-633. Foley, A. G., Murphy, K. J., Hirst, W. D., Gallagher, H. C., Hagan, J. J., Upton, N., . . . Regan, C. M. (2004). The 5-HT6 receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology, 29(1), 93-100. Halloran, J., Hussong, S. A., Burbank, R., Podlutskaya, N., Fischer, K. E., Sloane, L. B., ... & Galvan, V. (2012). Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience, 223, 102-113. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Pahor, M. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395. Hatcher, P. D., Brown, V. J., Tait, D. S., Bate, S., Overend, P., Hagan, J. J., & Jones, D. N. (2005). 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology, 181(2), 253-259. Hekimi, S., & Guarente, L. (2003). Genetics and the specificity of the aging process. Science, 299(5611), 1351-1354. Hoeffer, C. A., & Klann, E. (2010). mTOR signaling: at the crossroads of plasticity, memory and disease. Trends in neurosciences, 33(2), 67-75 Houtkooper, R. H., Williams, R. W., & Auwerx, J. (2010). Metabolic networks of longevity. Cell, 142(1), 9-14. Howell, J. J., & Manning, B. D. (2011). mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends in Endocrinology & Metabolism, 22(3), 94-102. Hursting, S. D., Lavigne, J. A., Berrigan, D., Perkins, S. N., & Barrett, J. C. (2003). Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annual review of medicine, 54(1), 131-152. Imai, S. I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 403(6771), 795-800. Jewell, J. L., & Guan, K. L. (2013). Nutrient signaling to mTOR and cell growth. Trends in biochemical sciences, 38(5), 233-242. Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493(7432), 338-345. Kaeberlein, M., McVey, M., & Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & development, 13(19), 2570-2580. Kim, D. H., & Sabatini, D. M. (2004). Raptor and mTOR: subunits of a nutrient-sensitive complex. TOR, 259-270. Kim, S. G., Buel, G. R., & Blenis, J. (2013). Nutrient regulation of the mTOR complex 1 signaling pathway. Molecules and cells, 35(6), 463-473. Kumar, V., Zhang, M. X., Swank, M. W., Kunz, J., & Wu, G. Y. (2005). Regulation of dendritic morphogenesis by Ras–PI3K–Akt–mTOR and Ras–MAPK signaling pathways. Journal of Neuroscience, 25(49), 11288-11299. Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Guertin, D. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335(6076), 1638-1643. Laplante, M., & Sabatini, D. M. (2009). mTOR signaling at a glance. Journal of cell science, 122(20), 3589-3594. Loiseau, F., Dekeyne, A., & Millan, M. J. (2008). Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex. Psychopharmacology, 196(1), 93-104. López-Lluch, G., Irusta, P. M., Navas, P., & de Cabo, R. (2008). Mitochondrial biogenesis and healthy aging. Experimental gerontology, 43(9), 813-819. Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., ... & Duman, R. S. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329(5994), 959-964. Masoro, E. J. (2002). Caloric restriction: a key to understanding and modulating aging (Vol. 1). Elsevier. Mattson, M. P., LaFerla, F. M., Chan, S. L., Leissring, M. A., Shepel, P. N., & Geiger, J. D. (2000). Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends in neurosciences, 23(5), 222-229. Mayeux, R., Costa, R., Bell, K., Merchant, C., Tang, M. X., & Jacobs, D. (1999). Reduced risk of Alzheimer's disease among individuals with low caloric intake. Neurology, 52(6), A296-A297. Meffre, J., Chaumont‐Dubel, S., la Cour, C. M., Loiseau, F., Watson, D. J., Dekeyne, A., ... & Hervé, D. (2012). 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO molecular medicine, 4(10), 1043-1056. Masoro, E. J. (2000). Caloric restriction and aging: an update. Experimental gerontology, 35(3), 299-305. Metaxakis, A., & Partridge, L. (2013). Dietary restriction extends lifespan in wild-derived populations of Drosophila melanogaster. PloS one, 8(9), e74681. Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes & development, 20(2), 174-184. Prolla, T. A., & Mattson, M. P. (2001). Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends in neurosciences, 24, 21-31 Roe, F. J. C., Lee, P. N., Conybeare, G., Kelly, D., Matter, B., Prentice, D., & Tobin, G. (1995). The Biosure Study: influence of composition of diet and food consumption on longevity, degenerative diseases and neoplasia in Wistar rats studied for up to 30 months post weaning. Food and Chemical Toxicology, 33, S1-S100. Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., ... & Woods, A. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science, 326(5949), 140-144. Smith, J. S., Brachmann, C. B., Celic, I., Kenna, M. A., Muhammad, S., Starai, V. J., ... & Boeke, J. D. (2000). A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proceedings of the National Academy of Sciences, 97(12), 6658-6663. Sohal, R. S., & Weindruch, R. (1996). Oxidative stress, caloric restriction, and aging. Science (New York, NY), 273(5271), 59. Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PloS one, 5(4), e9979. Stanfel, M. N., Shamieh, L. S., Kaeberlein, M., & Kennedy, B. K. (2009). The TOR pathway comes of age. Biochimica et Biophysica Acta (BBA)-General Subjects, 1790(10), 1067-1074. Tang, G., Gudsnuk, K., Kuo, S. H., Cotrina, M. L., Rosoklija, G., Sosunov, A., ... & Tissenbaum, H. A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410(6825), 227-230 Tucci, P. (2012). Caloric restriction: is mammalian life extension linked to p53? Aging (Albany NY), 4(8), 525-534. Weindruch, R., Walford, R. L., Fligiel, S., & Guthrie, D. (1986). The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutrition, 116(4), 641-54. Yang, F., Chu, X., Yin, M., Liu, X., Yuan, H., Niu, Y., & Fu, L. (2014). mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits. Behavioural brain research, 264, 82-90. Yu, Z.F. and Mattson, M.P. (1999) Dietary restriction and 2-deoxyglucos administration reduce focal ischemic brain damageand improve behavioral outcome: evidence for a preconditioningmechanism. J. Neurosci. Res. 57, 830–839. Yue, Z. (2014). Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 83(5), 1131-1143. Zhang, C., Wendel, A. A., Keogh, M. R., Harris, T. E., Chen, J., & Coleman, R. A. (2012). Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Proceedings of the National Academy of Sciences, 109(5), 1667-1672. Zhu, H., Guo, Q., & Mattson, M. P. (1999). Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain research, 842(1), 224-229. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67645 | - |
dc.description.abstract | 飲食節制 (Dietary restriction) 的進食策略已被廣泛的證實在許多物種上具有減少老化相關疾病之發生率,以及延長壽命的功效。另外,其也能改善神經退化疾病的認知缺陷,增進記憶功能。本研究發現飲食節制在進行四週後,能顯著增進年輕小鼠的記憶功能,且此效果會因再度回復原本飲食而消失;另外,年老小鼠也能靠著飲食節制促進記憶功能。
根據本實驗室過去的發現,血清素第六型受體 (5-hydroxytryptamine receptor 6; HTR6) 在飲食節制中扮演調控的角色。在行為測量中,如同一般基因型飲食節制的小鼠,HTR6基因剔除的小鼠記憶表現較優良,且此基因剔除會消除飲食節制對記憶的正面效果,顯示HTR6為飲食節制效果的途徑所需。 而我們也發現,一控管營養代謝的訊號分子-mammalian target of rapamycin complex 1 (mTORC1) 漸漸被認為與認知功能有關,與飲食節制帶來的效果相符合,並接著推測其是否為HTR6所調控。本實驗取用一般基因型胎鼠腦神經細胞進行培養,發現以藥物抑制細胞之HTR6會減少mTORC1訊號的表現;另外,HTR6基因剔除小鼠的海馬迴組織也有相同的結果。而HTR6基因剔除的胎鼠細胞之mTORC1表現並不會被這些藥物影響。 行為實驗結果中,在HTR6基因剔除小鼠飲食裡加入mTORC1的促進劑會消除其記憶促進效果,而mTORC1的抑制劑則不會有進一步的影響。在一般基因型小鼠中,將mTORC1的促進劑以及抑制劑加入飲食,飲食節制便不會促進小鼠的記憶力,證實mTORC1參與在此效果中,而這些結果進一步說明了HTR6和mTORC1之在調控記憶功能的關聯。 而後,為了探究行為上的改變是否源自與腦神經中的變化,本研究進行海馬迴神經元結構的分析。實驗發現,飲食節制會使小鼠神經的樹突長度縮短,且誘發突觸密度增加,此結果部分解釋了其認知功能的變化。而在HTR6基因剔除的小鼠中,飲食節制對神經結構上的改變會被消除,表示HTR6為此神經結構變化所需。在一般基因型老鼠中進行mTORC1之藥物處理,發現飲食節制依然會縮短樹突長度,而對突觸脊密度的增加效果則會消失,表示HTR6-mTORC1訊號路徑會調控由飲食節制所誘發的記憶促進及突觸脊密度的改變。 總結來看,本研究證實了HTR6- mTORC1訊號路徑可能調控飲食節制所誘發的記憶促進效果。 | zh_TW |
dc.description.abstract | Dietary restriction (DR) has been widely demonstrated to extend life span and reduce incidence of age-related diseases in a variety of animal models. It has also been shown to promote memory function.
We began the study with demonstrating that DR could improve memory performance in both young and aged mice using the novel object recognition test. The DR manipulation took about four weeks to induce enhanced memory performance in young mice and the effect was diminished within two weeks after the mice had shifted to an ad libitum (AL) diet. In previous studies, we have identified serotonin (5-hydroxytrptamine) receptor, HTR6, may act as a critical regulator in DR-induced memory enhancement. HTR6 knockout (KO) mice under AL condition showed enhanced memory as seen in wild type (WT) DR mice, and DR did not further improve the memory performance of HTR6 KO mice.To further investigate the molecular mechanisms underlying DR and HTR6, we focused on mTORC1 signaling pathway, which is nutrient sensitive and have been shown to interact with HTR6. We found that pharmacological inhibition in dissected embryonic neurons and genetic deletion of HTR6 in hippocampal tissue led to a reduced deactivation of mTORC1 signaling, which resembled the result under condition of DR (fasting treatment in the cells). The mTORC1 signaling in primary neuronal cells from HTR6 KO exhibited an impaired response to HTR6 agonist and antagonist, but still reacted to phosphatidic acids (PA; mTORC1 activator) and rapamycin (mTORC1 inhibitor) addition. In the behavioral level, the PA supplementation reversed the memory improvement of HTR6 KO mice under AL condition while rapamycin did not exhibit additive effect. In WT mice, the DR treatment significantly enhanced memory compared to AL in the vehicle-fed mice. However, the difference was not seen in PA- and rapamycin-fed mice, which indicated that mTORC1 itself was required for the effects of DR. Taken these results together, the HTR6-mTORC1 interaction plays an essential role for DR-enhanced memory performance. Since cognitive performance is generally associated with morphological alterations in neurons, we further analyzed the structure of hippocampal neurons in both HTR6 KO and WT mice fed with AL or DR using the Golgi silver-impregnation method. In WT mice, we found that DR mice have shorter dendritic length and higher spine density compared to AL control. However, these differences were not seen in HTR6 KO mice under AL and DR, suggesting that HTR6 is required for DR-induced morphological changes. The neuronal morphology was also evaluated in PA and rapamycin-fed mice in AL and DR conditions. The effect of reduction in dendritic length induced by DR was not interfered by PA and rapamycin treatments. Nevertheless, DR-induced increased spine density was abolished in PA treated mice but unaltered in rapamycin treated mice. In summary, we propose a model that HTR6-mTORC1 pathway can mediate DR-induced memory enhancement at structural and behavioral levels. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T01:41:54Z (GMT). No. of bitstreams: 1 ntu-106-R04454002-1.pdf: 2622253 bytes, checksum: 5f50826771dcb1ac410dcf21ed0a8908 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 中文摘要 1
Abstract 3 Chapter 1 Introduction 8 1.1 Dietary Restriction 8 1.2 DR and cognitive functions 9 1.3 The mechanisms underlying DR 10 Chapter 2 Materials and Methods 12 2.1 Mice and food manipulation 12 2.2 Behavioral tests 13 2.2.1 Open field test 13 2.2.2 Novel object recognition test 13 2.3 Morphological analysis 14 2.3.1 Golgi-cox impregnation 14 2.3.2 Dendrite structurral analysis 15 2.3.3 Spine density analysis 15 2.4 Cresyl violet staining 16 2.5 Primary cortical neurons culture and drugs 16 2.6 Western blotting and antibodies 17 2.7 Statistical analysis 19 Chapter 3 Results 20 3.1 Dietary restriction improves memory function both in young and aged mice 20 3.1.1 The time course of DR-induced memory enhancement 20 3.1.2 DR improves memory performance in aged mice 21 3.2 5-hydoxytryptamine receptor 6 (HTR6) mediates DR -induced memory enhancement 22 3.2.1 DR-induced memory enhancement is nonexistent in HTR6 KO mice 22 3.2.2 Morphological analysis in WT and HTR6 KO mice 23 3.2.3 DR reduces neuronal dendritic length in WT mice while not in HTR6 KO mice 23 3.2.4 DR increases dendritic spine density in WT mice while not in HTR6 KO mice 24 3.2.5 DR does not affect cell density in WT and HTR6 KO in the hippocampus 25 3.3 Mammalian target of rapamycin complex1 (mTORC1) signaling mediates DR –induced memory enhancement 26 3.3.1 DR does not affect memory performance under pharmacological treatment of mTORC1 27 3.3.2 DR decreases expression of mTORC1 downstream signaling 28 3.3.3 The PA and rapamycin treatments do not affect the reduction of dendritic length elicited by DR, but abolish the alterations in spine density 29 3.4 mTORC1 interacts with DR-HTR6 pathway 30 3.4.1 Pharmacological manipulations on HTR6 influence the mTORC1 signaling 30 3.4.2 The PA treatment reverses the memory function in HTR6 KO mice 31 3.4.3 HTR6 regulates the mTORC1 signaling 32 Chapter 4 Discussion 33 Reference 59 | |
dc.language.iso | en | |
dc.title | HTR6-mTORC1訊號路徑在飲食節制誘發之記憶促進的角色 | zh_TW |
dc.title | The role of HTR6-mTORC1 pathway in dietary restriction-induced memory enhancement | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蔡亭芬(Ting-Fen Tsai),陳儀莊(Yi-juang Chern),潘俊良(Chun-Liang Pan) | |
dc.subject.keyword | 飲食節制,記憶,行為,訊號, | zh_TW |
dc.subject.keyword | dietary restriction,memory,behavior,signaling, | en |
dc.relation.page | 63 | |
dc.identifier.doi | 10.6342/NTU201701990 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-07-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 腦與心智科學研究所 | zh_TW |
顯示於系所單位: | 腦與心智科學研究所 |
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