Graduation Year

2011

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medical Sciences

Major Professor

Paula C. Bickford

Keywords

eyebling conditioning, mircroglia, morris water maze, neural stem cell, neurogenesis, radial arm water maze

Abstract

Studies have shown that there is a strong correlation between aging and neurodegenerative diseases. Aging is considered the number one risk factor to develop neuropathologies such as memory loss, senile dementia, Alzheimer's disease (AD), and Parkinson's disease. Neurodegenerative diseases tend to start during adulthood, and aggravate over time, making them difficult to prevent and to treat. In the Unites States, demographic studies by U.S. Bureau of the Census have determined that our aging population of >65 years is expected to increase from the present 35 million to 78 million in 2030. This would result, not only to an increase of age-related chronic illness, and mental disability, but to a decrease of quality of life, and an elevation of medical cost. Thus, this dissertation has focused on investigating the molecular mechanisms during the process of aging and its correlation to chronic inflammation and cognitive impairments. The etiology of neurodegenerative diseases is not very well understood, but research has shown that the process of aging is a key factor, which involved oxidative stress, an over reactive microglia, and increased production of pro-inflammatory cytokines. All these factors are known to decrease cell proliferation, which limit neuroplasticity and they might lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. Previously, we have shown that natural compounds such as polyphenols from blueberry, and green tea, and amino acids like carnosine are high in antioxidant and anti-inflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body. Therefore, we examined the hypothesis that the pro-inflammatory cytokine TNF-[U+F061] may be a critical factor that modulates classical conditioning behavior, the effects of NT-020 on adult neurogenesis, inflammatory markers of the CNS, and the effect of NT-020 on cognitive function as shown using spatial navigation task. The results show that in aged rats, endogenous production of pro-inflammatory cytokine TNF-α impairs the acquisition of learning and memory consolidation in the delay eyeblink classical conditioning task (EBC). It was shown that this effect can be replicated by infusing young rats with exogenous TNF-α prior to EBC. Using NT-020 as a dietary supplement for one month, it was found that NT-020 ameliorates the age-related impairments typically found in aged rats in the spatial navigation tasks Morris water maze and radial arm water maze. By looking at immunohistochemistry analysis, it was found a decreased number of OX6 MHC II positive cells, increased neurogenesis, and increased number of proliferating cells in the dentate gyrus (DG) of the hippocampus in the aged rats fed with NT-020 relative with their counterpart aged control. In the CNS, Inflammatory markers were analyzed, and it was found that aged rat fed with NT-020 supplemented diet has decrease levels of pro-inflammatory cytokines in compared with aged rats fed with NIH-31 control diet. In conclusion, TNF-α, a pro-inflammatory cytokine has shown to have a modulatory effect during classical conditioning. Moreover, NT-020 may promote a healthy CNS milieu, proliferation of neuronal progenitors, and maintenance of nature neurons in the aged rats and it might exert anti-inflammatory actions which promote a functional stem cell pool in the CNS of aged rats.

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