Assessment of Second Messenger Function in the Hippocampus of Aged Rats with Cognitive Impairment

Excerpt

The hippocampus is an anatomical region that is critical for certain types of learning and memory that are vulnerable to the effects of normal aging. Early data indicated that these cognitive deficits could be attributed to age-related neuronal loss. However, in the mid-1990s, it was discovered that frank neural degeneration was not a consequence of the normal aging process. First observed in rodents, this finding has since been replicated in primates, including humans (reviewed in [1] and [2]). Given the fact that hippocampal neuronal number is relatively preserved, even at very advanced ages, dysfunctions associated with neuronal integrity (e.g., proper encoding, gene expression and cell signaling) have become an important avenues of exploration as causative factors of age-related mnemonic impairment [3–5]). Indeed, as this chapter discusses in detail, age-related deficits in signal transduction do occur and are presumed to reflect deficient transfer of information both within the hippo-campal formation and between the hippocampus and other brain structures critical for proper cognitive function (e.g., [6–8]).

The animal model that we have used to investigate the behavioral relevance of age-related changes in signal transduction mechanisms is reliable and well-established [9, 10]. Briefly, hippocampal-dependent spatial memory is assessed in young and aged male Long-Evans rats in the Morris water maze. Using data from probe trials that are interpolated throughout our training protocol, an individual measure of spatial learning ability is derived for each rat (i.e., a “spatial learning index”). As shown in Figure 9.1, plotting individual young and aged rat spatial performance using the spatial learning index reveals that this measure reliably distinguishes two groups of aged rats: (1) those that learn on par with the young cohorts (i.e., aged-unimpaired rats) and (2) those that perform outside the range of young rats, demonstrating impairment on the task (i.e., aged-impaired rats) [9]. The variability in spatial learning performance observed in this population of aged rats both mimics that observed in humans and affords investigators the opportunity to not only compare neurobiological factors that change as a function of age but, also, to directly link such changes to a functional behavioral measure of hippocampal integrity. Among aged rats, the correlation between individual learning indices and neurobiological measures related to the efficacy of signal transduction mechanisms is the primary methodology used in our studies. Although all data in this chapter are related to this one particular model, both the neurobiological and behavioral changes have been replicated in other strains of rodents and even primates. The approaches and techniques described here should be useful and applicable to other animal models of cognitive aging.