Animal models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry

Alzheimer's disease (AD) occurs against a background of cognitive and neurobiological aging. Animal models of normal aging may be used to study the neurobiological structures that are most involved in AD pathology, i.e. hippocampal/cortical systems. For example, spatial learning is dependent upon the integrity of the hippocampus, a structure that is much affected in humans with AD. Spatial learning tasks, such as the Morris water maze, have been used to screen aged rats for cognitive status prior to neurobiological assessment of hippocampal circuitry. Manifestations of the aging process, which are often minimal or entirely obscured in studies comparing young and aged brains, become apparent when the cognitive status of aged animals is taken into account. For example, studies examining the septohippocampal cholinergic system in behaviorally-characterized rodents have shown that there is a decline in many markers for these cholinergic neurons that coincides with severity of spatial learning impairment. Another advantage of cognitive assessment in animal models used to study aging is that it may help to distinguish between those neurobiological changes that are functionally detrimental and those that may represent compensatory adaptations to maintain cognitive function. Age-related changes in two neurobiological measures in the hippocampus are discussed in this report. Alterations in the opioid peptide dynorphin (increased peptide content and prodynorphin mRNA) in hippocampus may contribute to impairment in that the greatest changes occur in those aged rats with severe spatial learning deficits. In contrast, a decrease in hippocampal [³H]kainate binding may represent an adaptive compensatory response because it is most evident in aged rats with preserved spatial learning ability. The use of such animal models can advance our understanding of aging processes and has important implications for the development of therapeutic interventions.