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vii
Figure 18. ERK1/2 inhibition primarily attenuates necrosis ....................................49
Figure 19. A model for SIRT1 regulation of IGF-I signaling...................................50
Figure 20. Reduced oxidative damage in SIRT1 knockout mouse brain .................51
Figure 21. SIRT1 inhibition decreases survival in paraquat induced oxidative stress ..........................................................................................................................53
Figure 22. Reduced life span of SIRT1 knockout mice under ad-lib and calorie restriction conditions .....................................................................................54
Figure 23. SIRT1 deficiency does not change gross brain anatomy .........................79
Figure 24. SIRT1KO mice exhibit impaired immediate memory in Y maze test .............................................................................................................................81
Figure 25. SIRT1KO mice exhibit impaired contextual fear ....................................83
Figure 26. SIRT1KO mice exhibit decreased conditioned fear to auditory cue .......84
Figure 27. SIRT1KO mice show impaired spatial learning in Barnes maze test .............................................................................................................................86
Figure 28. Differential search strategies employed by WT and SIRT1KO mice in Barnes maze test...........................................................................................88
Figure 29. SIRT1 protein levels in the hippocampus of NeSTO mice .....................90
Figure 30. SIRT1 overexpression in hippocampal neurons of NeSTO mice ...........91
Figure 31. Overexpression of SIRT1 does not alter spontaneous exploratory and locomotor activities ............................................................................................93
Figure 32. SIRT1 overexpression in the brain does not alter associative memory .....................................................................................................................94
Figure 33. Effect of SIRT1 overexpression on performance in 14-unit T-maze test .............................................................................................................................96
Figure 34. Effect of SIRT1 overexpression on performance in Morris water maze test....................................................................................................................97
Figure 35. SIRT1 deficiency has no effect on input/output properties at Schaffer collateral CA1 synapses .............................................................................98
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 7 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | vii Figure 18. ERK1/2 inhibition primarily attenuates necrosis ....................................49 Figure 19. A model for SIRT1 regulation of IGF-I signaling...................................50 Figure 20. Reduced oxidative damage in SIRT1 knockout mouse brain .................51 Figure 21. SIRT1 inhibition decreases survival in paraquat induced oxidative stress ..........................................................................................................................53 Figure 22. Reduced life span of SIRT1 knockout mice under ad-lib and calorie restriction conditions .....................................................................................54 Figure 23. SIRT1 deficiency does not change gross brain anatomy .........................79 Figure 24. SIRT1KO mice exhibit impaired immediate memory in Y maze test .............................................................................................................................81 Figure 25. SIRT1KO mice exhibit impaired contextual fear ....................................83 Figure 26. SIRT1KO mice exhibit decreased conditioned fear to auditory cue .......84 Figure 27. SIRT1KO mice show impaired spatial learning in Barnes maze test .............................................................................................................................86 Figure 28. Differential search strategies employed by WT and SIRT1KO mice in Barnes maze test...........................................................................................88 Figure 29. SIRT1 protein levels in the hippocampus of NeSTO mice .....................90 Figure 30. SIRT1 overexpression in hippocampal neurons of NeSTO mice ...........91 Figure 31. Overexpression of SIRT1 does not alter spontaneous exploratory and locomotor activities ............................................................................................93 Figure 32. SIRT1 overexpression in the brain does not alter associative memory .....................................................................................................................94 Figure 33. Effect of SIRT1 overexpression on performance in 14-unit T-maze test .............................................................................................................................96 Figure 34. Effect of SIRT1 overexpression on performance in Morris water maze test....................................................................................................................97 Figure 35. SIRT1 deficiency has no effect on input/output properties at Schaffer collateral CA1 synapses .............................................................................98 |
