Rodent models of brain aging and neurodegeneration

Abstract

Laboratory rats and mice have long been considered to be convenient models for the study of aging in various mammalian systems. With regard to functions of the central nervous system, rodents have anatomical, cellular, and molecular characteristics that are similar to humans, and they can be tested for behavioral analogues of basic human motivational, reflexive and psychomotor functions, as well as for higher-order brain functions such as learning, memory and cognition. Behavioral studies of rodents conducted in the 1970’s and 1980’s provided confirmation that rodents indeed exhibit age-related declines in cognitive and psychomotor functions across their relatively short life spans. While it was clear that these declines did not reflect neurodegenerative conditions like Alzheimer’s or Parkinson’s diseases, it nevertheless became feasible to study the biological basis of the age related impairments in higher-order brain functions of these species. Moreover, rodent models of brain aging were recognized as potentially useful for predicting the effectiveness of therapeutic interventions on functional aging in humans. Research focused on age-related neurodegenerative diseases moved in a different direction, employing anatomical, pharmacological, and genetic manipulations to mimic neurodegenerative conditions. However, the behavioral characterization of the rodent models at different ages has been an essential element in both types of research, and has provided the most critical evidence needed to evaluate hypotheses about the neurobiological basis of brain aging and neurodegenerative disease. Efforts employing rodent models to identify the causes of brain aging and neurodegenerative conditions gained significant momentum in the 1990s, and many research programs and their methods of investigation have matured during the first half of the current decade. Three of the papers in the current issue discuss methodological approaches based on an earlier observation that age-related declines of cognitive function in rodents differ in severity among individuals, as appears to be the case in human subjects. Such trends are often reflected in an age-related increase of variability between test subjects, or as the presence of an apparent subset of aged animals that show reliable cognitive impairment. The application of methods to identify the specific neurobiological substrates that correlate with individualized cognitive performance of old rodents has led to significant advances in understanding of the effects and potential causes of brain aging. In particular, one article in this issue illustrates some novel insights gleaned through implementation of this type of methodology in conjunction with microarray profiling. A traditional approach to understanding processes of biological aging has been to study models or conditions in which the timetables of various age-related endpoints appear to be decelerated or accelerated. Such approaches have been equally attractive in brain aging and neurodegeneration research, as illustrated in two review articles in the current issue. These reviews provide new insights with regard to the potential influence of cerebral ischemia and disrupted circadian rhythms on cognitive function during aging. Long-standing practical and theoretical issues regarding the use of rodent models in aging research are widely considered in this issue. The availability of aged mice and rats as a critical resource has permitted a remarkable growth in brain aging research programs, but has simultaneously (and quite unavoidably) influenced the nature of the investigations by virtue of the specific genotypes that have been available. Articles in the current issue illustrate the use of a variety of different mouse and rat genotypes and discuss the extent to which they are appropriate models when used in different types of brain aging or neurodegeneration research. Additionally, one article illustrates assessment of decline in cognitive and psychomotor function in aging non-human primates, and addresses theoretical issues having a significant impact on the validity of various rodent models of brain aging. The common element among the articles appearing in this issue is a focus on behavioral assessment of aging in higher-order functions of the brain, the organ that must be considered closely linked to many important components of successful aging. While the life span has been considered a “gold standard” for evaluating potential anti-aging interventions in rodents, assessment of life span alone may fail to fully address the critical question of whether or not the productive, independent periods of life can be extended. While diverse in their individual focus, the articles in this issue are all reflective of progress toward an improved “standard” for understanding and predicting successful aging.