Page 19 |
Save page Remove page | Previous | 19 of 144 | Next |
|
small (250x250 max)
medium (500x500 max)
Large (1000x1000 max)
Extra Large
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
|
9
brain slice preparations. It is commonly studied in the Schaffer collateral pathway between CA3 pyramidal neurons and CA1 area in the adult hippocampus. When a high frequency stimulation (HFS, for example, 100 Hz lasting 1 second) or theta burst stimulation (TBS) is applied the amplitude of excitatory postsynaptic potential (EPSP) or the slope of the rising phase of EPSP becomes enhanced compared to that recorded before the delivery of this induction stimulation. This “potentiation’ of synaptic strength can last for hours, days or even longer depending on the preparations and induction protocol used, hence the term long term potentiation (Bliss and Collingridge, 1993).
The induction of classical LTP depends on NMDA receptors that act as a coincidence detector. Following HFS, glutamate, the excitatory neurotransmitter released by presynaptic terminals, bind to AMPA receptors on the postsynaptic neurons, which in turn allow sodium (Na+) ions to enter the cells and depolarize the membrane to such an extent that magnesium (Mg2+) ions, which usually block the NMDA receptors, are expelled. The simultaneous removal of magnesium and binding of glutamate to NMDA receptors during HFS thus trigger an influx of calcium (Ca2+) into the cells. The Ca2+ influx leads to a complicated cascade of signaling events at postsynaptic sites which are still not well understood. Based on published studies, the activation of multiple protein kinases are critical to this process, including protein kinase C (PKC), protein kinase A (PKA), extracellular signal-regulated kinases (ERK1/2) and phosphoinositide 3-kinases (PI3K), et cetera. As a result, AMPA receptors are modified and inserted onto the postsynaptic membranes. The increase in the number of AMPA receptors on postsynaptic
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 19 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 9 brain slice preparations. It is commonly studied in the Schaffer collateral pathway between CA3 pyramidal neurons and CA1 area in the adult hippocampus. When a high frequency stimulation (HFS, for example, 100 Hz lasting 1 second) or theta burst stimulation (TBS) is applied the amplitude of excitatory postsynaptic potential (EPSP) or the slope of the rising phase of EPSP becomes enhanced compared to that recorded before the delivery of this induction stimulation. This “potentiation’ of synaptic strength can last for hours, days or even longer depending on the preparations and induction protocol used, hence the term long term potentiation (Bliss and Collingridge, 1993). The induction of classical LTP depends on NMDA receptors that act as a coincidence detector. Following HFS, glutamate, the excitatory neurotransmitter released by presynaptic terminals, bind to AMPA receptors on the postsynaptic neurons, which in turn allow sodium (Na+) ions to enter the cells and depolarize the membrane to such an extent that magnesium (Mg2+) ions, which usually block the NMDA receptors, are expelled. The simultaneous removal of magnesium and binding of glutamate to NMDA receptors during HFS thus trigger an influx of calcium (Ca2+) into the cells. The Ca2+ influx leads to a complicated cascade of signaling events at postsynaptic sites which are still not well understood. Based on published studies, the activation of multiple protein kinases are critical to this process, including protein kinase C (PKC), protein kinase A (PKA), extracellular signal-regulated kinases (ERK1/2) and phosphoinositide 3-kinases (PI3K), et cetera. As a result, AMPA receptors are modified and inserted onto the postsynaptic membranes. The increase in the number of AMPA receptors on postsynaptic |
