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either vision problems or activity levels. These data, therefore, implicate the essential role of SIRT1 in hippocampus-dependent learning and memory. In the Barnes maze test although we could not record the amount of time each mouse spent in different quadrants of the maze, a reduced success rate, increased latency, the non-declining deviation as well as the limited acquirement of spatial search strategy exhibited by SIRT1 KO mice all clearly manifest the role of SIRT1 in this type of spatial learning. In contrast, auditory fear conditioning relies on the amygdala (Huang et al., 2008). In SIRT1 KO mice the decrease in freezing response to auditory cue, although to a lesser degree, may imply that SIRT1 in other brain regions such as the amygdala also played a part. Consistent with our data, preliminary results from Dr. Michael Mcburney's lab also suggest that SIRT1 KO mice show a deficit in certain forms of learning (data not shown). Although SIRT1 KO mice have brains which are 20% smaller than in WT controls (Boily et al., 2008a), we did not detect visible alterations in the neuroanatomical architecture of the brain nor in neuronal morphology. In the current study we focused on the hippocampus, however, other brain regions may also be assessed in future studies. Specifically, better antibodies or other probes of SIRT1 need to be developed to reveal the location of SIRT1 in different brain regions since SIRT1 may exhibit a differential distribution in different brain regions. Moreover, the subcellular distribution of SIRT1 (for instance, nuclear versus cytosolic) may also be different in different brain regions and a detailed characterization will be desirable. The exact localization of SIRT1 in neurons, for example nuclear, pre-synaptic or post-synaptic locations, will provide us with different clues on its functional mechanisms. In addition, considering the ubiquitous knocking out
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 118 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 108 either vision problems or activity levels. These data, therefore, implicate the essential role of SIRT1 in hippocampus-dependent learning and memory. In the Barnes maze test although we could not record the amount of time each mouse spent in different quadrants of the maze, a reduced success rate, increased latency, the non-declining deviation as well as the limited acquirement of spatial search strategy exhibited by SIRT1 KO mice all clearly manifest the role of SIRT1 in this type of spatial learning. In contrast, auditory fear conditioning relies on the amygdala (Huang et al., 2008). In SIRT1 KO mice the decrease in freezing response to auditory cue, although to a lesser degree, may imply that SIRT1 in other brain regions such as the amygdala also played a part. Consistent with our data, preliminary results from Dr. Michael Mcburney's lab also suggest that SIRT1 KO mice show a deficit in certain forms of learning (data not shown). Although SIRT1 KO mice have brains which are 20% smaller than in WT controls (Boily et al., 2008a), we did not detect visible alterations in the neuroanatomical architecture of the brain nor in neuronal morphology. In the current study we focused on the hippocampus, however, other brain regions may also be assessed in future studies. Specifically, better antibodies or other probes of SIRT1 need to be developed to reveal the location of SIRT1 in different brain regions since SIRT1 may exhibit a differential distribution in different brain regions. Moreover, the subcellular distribution of SIRT1 (for instance, nuclear versus cytosolic) may also be different in different brain regions and a detailed characterization will be desirable. The exact localization of SIRT1 in neurons, for example nuclear, pre-synaptic or post-synaptic locations, will provide us with different clues on its functional mechanisms. In addition, considering the ubiquitous knocking out |
