There is substantial evidence that specific factors that adversely impact cognition in rat models also correlate with age-related cognitive impairment in primates, including humans. For example, assessment of the degree of atrophy of the medial temporal lobe in humans is an effective predictor for the development of dementia in patients with mild cognitive impairment (Korf et al., 2004), and medial temporal lobe atrophy in stroke patients predicts poor cognitive performance (Jokinen et al., 2004). Likewise, lesions of medial temporal lobe structures induce memory impairments in rodents (reviewed by Jarrard, 1993). Moreover, age-related changes such as alterations in the glucocorticoid system and increases in oxidative stress are found among aged rat and human populations (Bizon et al., 2001; Nicolle et al., 2001; de Quervain et al., 1998; Roozendaal, 2002; de Quervain et al., 2003; Lupien et al., 2005).
Finally, as discussed in more detail below, the absence of frank neural loss among aged rats with memory impairment has now been replicated in aged monkeys and humans. It should be emphasized that although parallels exist between behavioral deficits observed in the rat models of aging discussed here and both rodent experimentally induced brain lesions and human age-related disease, the models we employ are not intended to represent human neurodegenerative disease such as Alzheimer's or Parkinson's disease. Rather, we consider these naturally occurring rat models a tool for understanding the normal aging process in the absence of disease. Some have suggested that the cognitive decline seen in these rat models is akin to what is referred to as nonprogressive mild cognitive impairment in humans, although additional research on neuronal atrophy and other defining characteristics in both rats and humans are needed to support the use of this terminology (Gallagher et al., 2003).
RAT AGING MODELS—STRAIN SELECTION
There is a plethora of rat strains commonly used in neurobiological research today, but special considerations need to be taken into account when choosing a rat strain in which to conduct cognitive aging research. The most popular strains used for aging research include Sprague Dawley, Fisher 344 (F344), Long-Evans, Brown Norway, and F344 x Brown Norway F1 (Bizon and Gallagher, 2005; Merrill et al., 2003; Drapeau et al., 2003; Kasckow et al., 2005; Lichtenwalner et al., 2001). Some critical factors to consider when selecting a rat strain include variability in health and lifespan inherent to the strain, strain-specific and sex-specific differences in cognition, and supplier availability. For example, certain strains may be more prone to tumors of the pituitary gland, a factor that can cause variability in circulating hormone levels and blindness through compression of the optic nerve. Such factors can impact cognitive performance and neurobiological data if behavioral tests are not carefully designed and aged rats are not properly screened for such tumors at sacrifice. Another consideration is the sex of rats chosen; the endocrine system certainly can influence memory and brain function, and it is well established that the endocrine system in rats, as in humans, is modified with aging. When using aged female rats one must therefore take into consideration circulating hormone levels in young and aged rats, as the estrous cycle in females is cyclic in young rats, becomes erratic at middle ages, and ceases at later ages (Savonenko and Markowska, 2003). Finally, availability must be a consideration for those wishing to conduct cognitive aging research. Indeed only three rat strains (F344, Brown Norway and F344 x Brown Norway F1 hybrids) are currently available for funded research from the National Institutes for Aging at the National Institutes of Health. Although we use the Long-Evans strain, which must be purchased as retired breeders (10-12 months of age) and then housed in the home institution, the latter can be an expensive and time-consuming option, as per diem expenses and long-term health monitoring for pathogens can become costly. Nevertheless, if the weaknesses of each strain are known (tendency for tumors, etc.), the behavioral characterization is soundly conducted, and aged rats are properly excluded due to poor health, the approach we describe below with Long-Evans rats should hold across strains.
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