Sunita Sharma

Date of Award

7-15-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology, Physiology and Therapeutics

First Advisor

Holly Brown-Borg

Abstract

The US Census Bureau projects that there Will be 71.5 million people over the age of 65 by 2030. One of the most significant problems is that the elderly population suffers from age-associated cognitive impairment. The hippocampus is one identified brain region known to be vulnerable to aging and is associated with a decline in growth hormone/insulin like growth factor-1 (GH/IGF-1), and an increase in oxidative stress and neuronal loss. The Ames dwarf mouse is a long-living animal that is growth hormone deficient and thus, lacks peripheral IGF-1. Ames mice have enhanced antioxidant protection in the peripheral system but the protection in the central nervous system is unclear. Considering the link between aging, memory, IGF-1 levels and oxidative stress, the experiments were designed to study learning and memory in long-living Ames mice. The results show that Ames dwarf mice use more spatial strategy, make fewer errors, and exhibit shorter escape latencies as compared to wild type mice in the Barnes maze and the T-maze. Spatial memory was maintained in the Ames dwarf mice following kainic acid (KA)-induced hippocampal neuronal loss. Even though kainic acid is known to induce oxidative stress, antioxidant enzymes like glutathione peroxidase were enhanced in KA-injected dwarf mice as compared to the saline-injected control group. In addition, wild type mice showed an increase in oxidative stress as indicated by the reduced ratio of glutathione: glutathione disulfide. There was no induction of Nrf-2 gene in the following KA in Ames dwarf mice further suggesting maintenance of antioxidant defense under oxidative stress conditions. In addition, Ames dwarf mice at young age showed significantly more neurogenesis following KA as compared to age-matched wild type controls. Taken together, this study provides valuable insight into the potential mechanisms of age associated cognitive decline and its relationship to antioxidant defense mechanisms in the central nervous system. A better understanding of these mechanisms could lead to the development of new therapeutic strategies to delay or prevent the development of age-related memory loss. This may be a first step towards improving the quality of life of the elderly population and achieve the ultimate goal of health care, promoting "health span".

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