Establishing a rodent (Fischer 344 rat) model of mild cognitive impairment in aging

Mild Cognitive Impairment is characterized by age-related decline in a variety of cognitive domains, including reference and working memory and olfactory function. Importantly, declining age-related mnemonic abilities is not inevitable; learning and memory deficits emerge in some people by middle-age while others remain largely cognitively-intact even at advanced chronological ages. The goal of this thesis is to establish a Fischer 344 (F344) rat model with some features of human cognitive aging which can then be utilized to undercover the neurobiological underpinnings of age-related cognitive deficits. Young (6 mo), middle-aged (11 mo), and aged (22 mo) F344 rats were behaviorally characterized in a well-established reference memory version of the Morris water maze task. Indeed, age-related impairments did occur across the lifespan. Moreover, the reference memory protocol used here was sufficiently sensitive to detect a difference in individual abilities among aged F344 rats such that approximately half of the rats performed on par with young while the other half performed outside this range, demonstrating impairment. These data mimic individual differences in declarative memory among aged humans. Subsequently, subsets of rats initially characterized on the reference memory version of the water maze were tested on either a spatial working memory water maze task or an olfactory discrimination task. Despite detecting an age-related delay-dependent decline in spatial working memory, this impairment was not correlated with spatial reference memory. In contrast, a strong and significant relationship was observed among aged rats in the odor discrimination task such that aged rats with the worst spatial reference memory were also the most impaired in their ability to discriminate odors for a food reward. Importantly, this subset of cognitively-impaired rats was not impaired on digging media discrimination problems with identical task demands, nor were they anosmic. These data are among the first to demonstrate a cross-domain cognitive deficit in a rodent model of human aging. Together, the current study both confirms the use of the naturalistic F344 rat model for the study of cognitive deficits within the context of aging and provides the most comprehensive cognitive profile of this rat population to date.