What Have We Learned So Far from Aging Place Cell Research

Although aged rats are certainly impaired in hippo-campal-dependent spatial memory, the hippocampus of aged rats does possess place cells with firing properties similar to those of young rats. Most importantly, the hippocampal cells of even the most spatially-impaired aged rats have place fields that are equally as crisp as those of young rats (see examples A1 and A2 of Figure 37.2; for a review of these data, see (Barnes, 1998)). The difficulties of cognitive aging, therefore, do not lie in simply a lack of spatial processing by the hippocampus. Instead, research has consistently shown that differences between the spatial representations of young and aged rats are brought out when the hippocampus is challenged to encode changes in the environment. In order to illustrate how place cells can be used as an effective tool in aging research, I will highlight three experiments that demonstrated these differences in hippocampal information processing and tied them to age-related memory impairments.

The experiment shown in Figures 37.2 and 37.3 was designed to draw a closer association between hippo-campal encoding of a new environment and the degree of age-related memory impairments in individual rats (Wilson et al., 2003). The spatial learning abilities of young and aged rats were determined by the water maze task; the young rats and some aged rats performed well, whereas other aged rats were significantly impaired (see Figure 37.3, the Y-axis).

Figure 37.3 The degree of place cell rigidity predicts the magnitude of spatial learning impairment. Similarity in place fields between exposures to the familiar cylinder and novel square are plotted against spatial learning performance in the water maze. Poor spatial memory is indicated by high spatial learning search error scores. Similarity scores (rigidity) correlated strongly with spatial memory performance of all groups combined (r(29) = 0.63, p < 0.001), and within the group of nine aged rats (r(17) = 0.55, p < 0.05). (Figure adapted from Wilson et a/., 2003.)

Figure 37.3 The degree of place cell rigidity predicts the magnitude of spatial learning impairment. Similarity in place fields between exposures to the familiar cylinder and novel square are plotted against spatial learning performance in the water maze. Poor spatial memory is indicated by high spatial learning search error scores. Similarity scores (rigidity) correlated strongly with spatial memory performance of all groups combined (r(29) = 0.63, p < 0.001), and within the group of nine aged rats (r(17) = 0.55, p < 0.05). (Figure adapted from Wilson et a/., 2003.)

Subsequently, hippocampal place cells were recorded as the rats explored a familiar environment (the cylinder) and a geometrically altered version of the environment (the square; see Figure 37.2, top row). Place fields of young and aged memory-intact rats changed upon exposure to the altered environment (Figure 37.2, cells Y1 and Y2). In contrast, many place fields of aged memory-impaired rats were unaffected by the environmental alteration (Figure 37.2, cells A1 and A2).

One possibility that must always be considered with aged rats is that the aged memory-impaired rats fail to use the visual landmarks in the water maze and place cell recordings because their vision is poor. The example in Figure 37.2, cell A2, illustrates why poor vision appears unlikely to account for the rigidity in the place cells in this experiment. The field was rigid during the first exposure to the square arena (Sq 1), but during the second exposure the field rotated with the landmarks (Sq 2). This indicates that the visual information could at least reach the hippocampus, but on some occasions it was not encoded properly.

To quantify this place field rigidity of aged rats, pixel-by-pixel correlation comparisons were done between the firing rate maps of the two environments. Place cells with different place fields in the cylinder and square environments had correlations near 0.0 (Figure 37.1, young cells Y1 and Y2), whereas place fields that are similar between the two environments had higher correlations approaching 1.0 (aged cells A1 and the first three trials of A2). These place cell characteristics of aged rats were then related to the abilities of the same rats on the spatial water maze. As Figure 37.3 shows, the degree of the rigidity in spatial representation predicted the magnitude of the spatial memory impairment. Thus, the heterogeneity of the spatial memory capacity with aging may be due to differential information encoding capacities by the young and aged hippocampus.

In a complement to these encoding difficulties, Barnes et al. (1997) have shown that, under other conditions, aged rats do not retrieve place cell representations properly. In an elegantly simple experiment, place cells were recorded in a familiar environment, and then the rats were taken on a tour of several new environments. When the rats were placed back into the familiar environment, the authors performed a correlation analysis between the place fields used initially in the familiar environment and those used after the new exposures. The young rats used the same place fields to represent both sessions in the familiar environment. The aged rats, on the other hand, recalled the former place fields correctly only about 70% of the time. On 30% of the occasions the aged rats used a completely novel arrangement of place fields to represent the familiar environment, suggesting a multistability of spatial representations in aged rats. As a control, the authors compared the place cell activity within uninterrupted sessions; in this case the aged rats, as well as the young, maintained the same spatial representations throughout the sessions. These results suggest that the aged rats had no difficulties maintaining a consistent representation during uninterrupted exposure to an environment, but that new experiences could interfere with successful recall of even a highly familiar environment.

To test how this place cell retrieval deficit related to spatial navigation abilities, the authors (Barnes et al., 1997) compared water maze data from 98 young and 93 aged rats (these rats were different individuals than those recorded). After four days of training, the young rats quickly found the hidden platform almost every time, whereas the aged rats sometimes found it and sometimes had much longer search paths. The variability of the aged rats was not due to between-rat differences, but rather each aged rat had good performances and bad performances. Together these data suggest that the aged rats sometimes got lost; that is, their place cells failed to recall the correct spatial representation, and this caused them to search incorrectly for the water maze platform.

In addition to difficulties encoding and retrieving place cell memories, aged rats are not as capable as young rats at making appropriate updates to their place cell representations during a continuous experience. Rosenzweig et al. (2003) recorded place cells of young and aged rats as they were actually performing a spatial navigation task. This cleverly designed experiment manipulated the relationship between external cues and self-motion cues. The goal location on a linear track remained constant with respect to the external visual cues, but the start box was shifted for each trial causing the walking distance to the goal location to vary. On each trial place fields were initially determined by the self-motion cues, and successful performance entailed a switch in the control of place fields from self-motion cues to external landmark cues well before the goal area was reached (Gothard et al., 1996). Young rats successfully updated their spatial representations, whereas many aged rats failed to update their representation to the relevant spatial information and therewith failed on the task. Furthermore, the learning of a goal location correlated strongly with how readily the place fields of the rats were adjusted into control by spatial cues.

This chapter has been intended to provide only examples of how place cells can be a useful tool for aging research; for more complete reviews of the aging place cell literature, please see Rosenzweig and Barnes (2003) and Wilson (2005). The experiments discussed here do serve to illustrate a rising theme from the literature: the hippocampus of aged rats is impaired in the processing of external environmental information. Under different demands on memory processing, this manifests itself in different forms (Wilson et al., 2004). Aged place cells that fail to change despite new environments allow us to see failures during encoding. The multistability of aged place cells upon return to a familiar environment allows us to see failures during recall. Aged place cells that do not readily adjust from self-motion to external landmark control allow us to see failures during updating of the representation. Place cells, therefore, provide a powerful window into the workings of memory in the aged hippocampus.

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