Individual differences in neurocognitive aging of the medial temporal lobe

Abstract

A wide spectrum of outcomes in the cognitive effects of aging is routinely observed in studies of the elderly. Individual differences in neurocognitive aging are also a characteristic of other species, such as rodents and non-human primates. In particular, investigations at behavioral, brain systems, cellular and molecular levels of analysis have provided much information on the basis for individual differences in neurocognitive aging among healthy outbred rats. These findings are likely to be relevant to an understanding of the effects of aging on the brain, apart from neurodegenerative conditions, such as Alzheimer's disease, which do not naturally occur in rodents. Here we review and integrate those findings in a model supporting the concept that certain features of cognitive decline are caused by distributed alterations in the medial temporal lobe, which alter the information processing functions of the hippocampal formation. An additional emerging concept from this research is that preserved abilities at older ages may depend on adaptive changes in the hippocampal system that distinguish successful aging.

Keywords: cognitive impairment; hippocampal formation; rats; spatial memory; successful aging.

Figure 1

Individual differences for cognitive aging in healthy rats. a Training trial performance for a group of young (6 months) and aged (28 months) male Long-Evans rats. Data points on the far left indicate performance on the first training trial, where no age difference was observed. The protocol consisted of three trials/day, with the last trial every other day consisting of a probe without the platform available for 30 s to monitor the rat’s spatial bias in searching for the platform location. b The learning index scores for individual rats in the young and aged groups obtained from probe trial performance to reflect search accuracy over the course of training. Note that the range of scores for aged rats encompasses and exceeds the range for the young, in the direction of impairment (higher index scores). c The retest scores from a probe trial after training 2 weeks later, with the platform in a new spatial location. In the re-test, data are presented for young rats and subgroups of aged rats based on the original learning index; aged rats that fell within the range of young performance are indicated as aged-unimpaired (AU), while aged rats that fell outside the range of young performance are designated impaired (AI). Aged rats that were impaired on the initial assessment were also impaired in the retest, while unimpaired aged rats again performed on a par with young. Note that the “search error” measure for training trials represents deviation from a direct path to the platform from the starting position, and that the learning index is calculated from probe trial search in X–Y coordinates (see Gallagher et al. for details). Data are reproduced from Colombo et al.

Figure 2

Retest in a novel spatial environment. Behaviorally characterized young and aged rats were tested after 1 month in an entirely novel spatial water maze environment (new maze in different physical location and surrounding cues, etc.). Rats received a single session of training (eight trials, 8 min intertrial interval), (a), using a visible platform that remained in a constant location with respect to extra-maze cues. During training trials all rats, irrespective of age or cognitive status, rapidly navigated to the escape platform (data not shown). Those data, similar to those for performance in other cue training protocols with a visible platform, show that the performance demands of the task are unaffected by aging. After a delay of 1 h, the rats were tested with the platform removed (b). Young rats and aged rats, originally characterized as “unimpaired” in the standardized protocol, swam directly to the location where the escape platform had been positioned in the earlier training session. In contrast, the previously characterized “impaired” aged rats did not navigate as accurately in the retention test (c), p<0.005). This study further demonstrates the reliability of differences in the aged population in a spatial memory assessment

Figure 3

Spatial memory in a radial-maze assessment. Data are shown for aged rats behaviorally characterized in the water maze and, 8 weeks later, tested on an eight-arm radial maze. The radial maze protocol was similar to that described in Chappell et al. (1998). After training both young and aged rats in the win-shift version of the radial maze task (each arm rewarded only once in a trial), we increased the memory demand of the task by imposing a brief delay during the trial. At the beginning of each trial a subset of arms was blocked; the identity and configuration of the blocked arms were varied across trials. Rats were allowed to obtain food on the arms to which access was permitted (Pre-Delay Information; a). Rats were then removed from the maze for a delay interval, during which time the barriers on the maze were removed, thus allowing access to all eight arms. Rats were then placed back onto the center platform and allowed to obtain the remaining food rewards (Post-Delay Memory; b). A memory error occurred after the delay when a rat returned to one of the arms that had been visited prior to the delay. Each rat’s performance was averaged across four consecutive trials, with a pre-delay information set of five open arms and delay interval of 60 s. Aged rats committed more memory errors than did young rats (p<0.025; on average, young rats committed 0.17 errors, whereas aged rats committed an average of 1.52 errors). Correlational analysis (Pearson’s r) was used to examine the relationship between performance of aged rats (N =10) in the radial maze and in the Morris water maze (learning index scores). The aged rats exhibited a wide range of performance on the radial maze (c), such that individual differences in this task were correlated with the prior water maze assessment (r=0.82, for aged rats; p<0.01)

Figure 4

Some of the connectional circuitry of the medial temporal lobe system. Studies in this research program have shown that aged rats, irrespective of cognitive status, have preserved numbers of neurons in both cortical (PHG, PR and EC) and hippocampal areas (DG, CA3, CA1). Our studies have also indicated no loss of connectional integrity, with the exception of input originating from layer II entorhinal cortical (EC) neurons. Specifically, aged rats with cognitive impairment have sparser input from that source terminating on both granule cells of the dentate gyrus (DG) and pyramidal neurons of the CA3 region (see text for further details and references). PHG parahippocampal/postrhinal cortex, PR perirhinal cortex, SUB subiculum

Figure 5

Multidimensional scaling plot of gene profiles in the CA3 region for young rats (black dots, N=7), aged unimpaired rats (red dots, N=7) and aged impaired rats (blue dots, N=8). In order to assess global similarity between CA3 RNA expression profiles, we calculated a Pearson’s correlation coefficient (r) for all pair-wise sample comparisons. This was done using gene expression metrics derived from G+C content-robust microchip average (GC-RMA) analysis (Qin et al. 2006) of Affymetrix microarrays (230-2.0 chips). A multidimensional scaling algorithm (MDS, using a distance metric of 1-r for each pair-wise comparison) was used to represent each CA3 RNA sample in two-dimentional space. Hence, each point in this plot represents the Affymetrix microarray data from a single CA3 RNA sample corresponding to an individual rat, and proximity reflects global similarity of gene expression profiles across samples/rats. The plot reveals a fairly clear separation of the three groups of animals studied, indicative of greater similarity in expression profiles within each group, and dissimilarity across the groups. The gene profiles of the aged impaired rats (blue dots) are entirely segregated from those of the young rats (black dots). Although the aged unimpaired rats performed on a par with young rats, there is little overlap between their gene expression profiles (red dots) and those of either young rats or aged cohorts with impaired cognition