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a digital video camera, located above the maze, on a fixed boom. Analysis was conducted from the resulting video files.
Maze pretraining. Before the start of preliminary one-way avoidance training in the straight runway, mice were removed from the colony room and transported, in their home cages, to the testing room where they were acclimated for at least 30 minutes (m). During the first trial, each mouse was transferred from its home cage to the start-box. The start-box was then inserted into the runway entrance and the mouse was gently pushed from the box into the runway. The mouse then had 10 seconds (s) to avoid a 0.8-mA foot-shock by running to the goal box at the opposite end of the runway. Once the mouse entered the goal box, a gate was lowered, and the entire box was transferred back to the runway entrance. All animals received 15 massed practice trials with a 1m intertrial interval (ITI) between 1000 and 1200 hours.
Maze acquisition. Maze training began 1 hr after the final pretraining session. During this interval, mice remained in the maze room (in their home cages). Prior to maze training, a shallow tray of ethanol was placed below the shock grid to discourage navigation via scent trails. During maze training, each mouse was removed from its home cage and placed into the start-box. The start box was then placed into the maze entrance and the mouse was gently pushed from the box. To avoid a continuous mild foot-shock (0.8 mA), the mouse had to navigate through the first gate in the maze within 10s. Once the mouse passed through the gate, it was lowered and the avoidance contingency was reset. This
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 82 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 72 a digital video camera, located above the maze, on a fixed boom. Analysis was conducted from the resulting video files. Maze pretraining. Before the start of preliminary one-way avoidance training in the straight runway, mice were removed from the colony room and transported, in their home cages, to the testing room where they were acclimated for at least 30 minutes (m). During the first trial, each mouse was transferred from its home cage to the start-box. The start-box was then inserted into the runway entrance and the mouse was gently pushed from the box into the runway. The mouse then had 10 seconds (s) to avoid a 0.8-mA foot-shock by running to the goal box at the opposite end of the runway. Once the mouse entered the goal box, a gate was lowered, and the entire box was transferred back to the runway entrance. All animals received 15 massed practice trials with a 1m intertrial interval (ITI) between 1000 and 1200 hours. Maze acquisition. Maze training began 1 hr after the final pretraining session. During this interval, mice remained in the maze room (in their home cages). Prior to maze training, a shallow tray of ethanol was placed below the shock grid to discourage navigation via scent trails. During maze training, each mouse was removed from its home cage and placed into the start-box. The start box was then placed into the maze entrance and the mouse was gently pushed from the box. To avoid a continuous mild foot-shock (0.8 mA), the mouse had to navigate through the first gate in the maze within 10s. Once the mouse passed through the gate, it was lowered and the avoidance contingency was reset. This |
