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68
around the maze and kept constant throughout the study. All mice were brought into the testing room 1 hour before the experiment. Each mouse was trained once daily from day 0 till day 7 and tested twice daily from day 1 through day 7. During the training session the mouse was placed in the middle of the maze in a start chamber for 30 sec and then allowed to freely explore the maze until it entered the EB or after 2 min elapsed. When the mouse entered the EB it was allowed to remain there for 30 sec. When the mouse did not enter the EB by itself it was gently guided there and allowed to stay there for 30 sec. The EB was always located underneath the same hole for a particular mouse. On days 1 to 7, following one training session the mice were tested twice. Testing was performed similarly to training, except that if after 2 min the mouse still did not enter the escape box it would not be guided to the EB but returned to the cage. Several measures were recorded for each testing including, the latency (second, s) (the time it took the mouse to enter the EB), the number of errors before entering the EB (errors were defined as nose pokes and head deflections over any false target box), deviation of the first error (how far away the first error was from the EB) and strategy employed by the mouse to locate the EB (random search strategy-localized hole searches separated by crossings through the maze center), serial search strategy-systematic hole searches in a clockwise or counterclockwise direction, or spatial search strategy-navigating directly to the EB with both error and deviation scores of no more than 3. Success rate for each test was either 100% (finding the EB within 2 min) or 0 (not finding the EB within 2 min). For mice that did not find the EB within 2 min the latency was represented as 120 (seconds). All measures were averaged from 2 tests to get the daily value for each mouse. Data were
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 78 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 68 around the maze and kept constant throughout the study. All mice were brought into the testing room 1 hour before the experiment. Each mouse was trained once daily from day 0 till day 7 and tested twice daily from day 1 through day 7. During the training session the mouse was placed in the middle of the maze in a start chamber for 30 sec and then allowed to freely explore the maze until it entered the EB or after 2 min elapsed. When the mouse entered the EB it was allowed to remain there for 30 sec. When the mouse did not enter the EB by itself it was gently guided there and allowed to stay there for 30 sec. The EB was always located underneath the same hole for a particular mouse. On days 1 to 7, following one training session the mice were tested twice. Testing was performed similarly to training, except that if after 2 min the mouse still did not enter the escape box it would not be guided to the EB but returned to the cage. Several measures were recorded for each testing including, the latency (second, s) (the time it took the mouse to enter the EB), the number of errors before entering the EB (errors were defined as nose pokes and head deflections over any false target box), deviation of the first error (how far away the first error was from the EB) and strategy employed by the mouse to locate the EB (random search strategy-localized hole searches separated by crossings through the maze center), serial search strategy-systematic hole searches in a clockwise or counterclockwise direction, or spatial search strategy-navigating directly to the EB with both error and deviation scores of no more than 3. Success rate for each test was either 100% (finding the EB within 2 min) or 0 (not finding the EB within 2 min). For mice that did not find the EB within 2 min the latency was represented as 120 (seconds). All measures were averaged from 2 tests to get the daily value for each mouse. Data were |
