Date of Award

5-2011

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Pharmacology and Neuroscience

Department

Graduate School of Biomedical Sciences

First Advisor

Nathalie Sumien

Abstract

Purpose: Obesity is an adverse health condition characterized by excessive weight gain. Aside from the pathological conditions most commonly associated with obesity, recent epidemiological studies have suggested that obesity may be associated with impaired learning and memory. Previous research has linked inflammation and oxidative stress, cellular changes that occur consequent to obesity, to impaired cognitive function. Obese rodent models have been established and are commonly used for obesity-related research; however, with respect to the effect of obesity on cognitive function, the data remain inconclusive. In these studies, two obese mouse models, representing two obesity-inducing causes: genetic vs. environment, were behaviorally characterized in order to determine which model was best suited to study behavioral and cellular changes associated with obesity. Furthermore, a suitable model needed to be identified to carry on studies focusing on the relation between aging and obesity, as one would predict an exacerbation of the impairment in old obese models with age. The current studies were also based on the rationale that a dietary intervention at mid-life would ameliorate behavioral and biochemical changes observed with obesity.

Methods: In study I, separate groups of 6-month old male and female C57BL/6 and leptin-deficient (ob/ob) were subjected to a battery of behavioral tests for motor, cognitive and visual function. In study II, separate groups of male C57BL/6 mice aged to 6- or 12-months were fed ad libitum either a control diet or a high-fat diet since 6- weeks of age. In a subset of the aged mice, a dietary intervention was introduced such that these mice were switched from the high-fat diet to the control diet at 6-months of age. Mice were subjected to a battery of behavioral tests at 6- or 12-months that required utilization of various component of memory, learning and visual function. Results: In study I, cognitive impairments were observed in the obese mice, and were exacerbated in female mice. While overall spatial learning was unaffected, male and female ob/ob mice performed worse on an active avoidance paradigm, indicating frontal cortical impairment. The ob/ob mice also performed worse on vision-associated tests. The results from this study suggested that obesity impairs cognitive and visual function in a sex-dependent manner. In study II, increased anxiety was observed in diet-induced obese mice; however, spontaneous activity, spatial capacity and performance on the active avoidance paradigm were unaffected. The dietary intervention reversed the effect of obesity on anxiety-like behaviors, but failed to improve cognitive and motor function. Visual impairments were observed in diet-induced obese mice, and these impairments were exacerbated with age. The results from study II indicated that diet- induced obese mice could be used to study the effects of obesity on visual, but not cognitive function.

Conclusions: Overall, the hypothesis that obesity impairs cognitive function and exacerbates age-related impairments was not supported and the dietary intervention had minor effects. However, in both models, obesity impaired visual function and it was exacerbated at older ages. These findings suggest that ob/ob and diet-induced obese mice are valid animal models for investigating obesity-induced visual disorders.

Comments

Elolf, Lauren M., The association between obesity, cognition and visual function. Doctor of Philosophy (Biomedical Sciences), March, 2011, 218 pp., 4 tables, 27 figures, bibliography, 255 titles.

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