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impaired to some degree. LTP is believed to be one of the mechanisms underlying memory and this finding is in line with the results from behavioral tests. We also checked if learning and memory is augmented in brain specific SIRT1 overexpressing mice. SIRT1 overexpression did not change the performance in fear conditioning, nor did it appear to substantially alter the performance in two different spatial tasks. Consistent with that, the synaptic plasticity in these mice did not change significantly. These results suggest that SIRT1 is important for synaptic plasticity and learning and memory, although enhancement of its activity may not be sufficient to improve these functions. Some research may be done in the future to enable us to further understand how exactly SIRT1 regulates learning and memory. For example, a brain specific or conditional SIRT1 knockout mouse may be used to confirm the deficit in cognitive functions. The SIRT1 overexpressing mice may be tested more carefully and comprehensively for behavior in learning and memory tasks. More importantly, the exact mechanism by which SIRT1 regulates synaptic plasticity needs further analysis. To start with, better SIRT1 antibodies should be utilized to map the distribution of SIRT1 in different brain regions. Here we examined the hippocampus but cortex, amygdala and other regions should also be checked and it would not be surprising to see different patterns in different areas. Next, the subcellular distribution of SIRT1 may not be the same in different brain regions and localizing SIRT1 to the nucleus, pre-synaptic or post-synaptic sites will have different functional implications. To figure out how SIRT1 may be involved in LTP, we can test in SIRT1 null hippocampus slices for any change in the pre-synaptic release of glutamate, the major excitatory transmitter, or in the activity or/and number of the post-
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 127 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 117 impaired to some degree. LTP is believed to be one of the mechanisms underlying memory and this finding is in line with the results from behavioral tests. We also checked if learning and memory is augmented in brain specific SIRT1 overexpressing mice. SIRT1 overexpression did not change the performance in fear conditioning, nor did it appear to substantially alter the performance in two different spatial tasks. Consistent with that, the synaptic plasticity in these mice did not change significantly. These results suggest that SIRT1 is important for synaptic plasticity and learning and memory, although enhancement of its activity may not be sufficient to improve these functions. Some research may be done in the future to enable us to further understand how exactly SIRT1 regulates learning and memory. For example, a brain specific or conditional SIRT1 knockout mouse may be used to confirm the deficit in cognitive functions. The SIRT1 overexpressing mice may be tested more carefully and comprehensively for behavior in learning and memory tasks. More importantly, the exact mechanism by which SIRT1 regulates synaptic plasticity needs further analysis. To start with, better SIRT1 antibodies should be utilized to map the distribution of SIRT1 in different brain regions. Here we examined the hippocampus but cortex, amygdala and other regions should also be checked and it would not be surprising to see different patterns in different areas. Next, the subcellular distribution of SIRT1 may not be the same in different brain regions and localizing SIRT1 to the nucleus, pre-synaptic or post-synaptic sites will have different functional implications. To figure out how SIRT1 may be involved in LTP, we can test in SIRT1 null hippocampus slices for any change in the pre-synaptic release of glutamate, the major excitatory transmitter, or in the activity or/and number of the post- |
