he number of individuals older than 65 years is projected to exceed 71.5 million in the year 2030, which is twice the number alive during the year 2000. While this dramatic increase in the number of individuals at risk for Alzheimer and vascular disease will pose a significant challenge to the health care industry, many older individuals will not actually die of these age-related dementias. Instead, a significant proportion of those older than 65 years will have to cope with alterations in memory function that are associated with normative aging. A clear understanding of the neurobiological mechanisms underlying normal age-related changes will be essential in helping elderly populations maintain cognitive performance with increasing age. This review covers the major age-related alterations in the hippocampus, a critical structure for learning and memory.

Malnutrition has been associated with a variety of functional and anatomical impairments of the hippocampal formation. One of the more striking of these is widespread loss of hippocampal neurons in postnatally malnourished rats. In the present study we have investigated the effect of prenatal malnutrition on these same neuronal populations, neurons that are all generated during the period of the dietary restriction. In prenatally protein deprived rats, using design-based stereology, we have measured the regional volume and number of neurons in the hilus of the dentate gyrus and the pyramidal cell layers of CA3, CA2, CA1, and the subiculum of 90-day-old animals. These results demonstrated a statistically significant reduction of 20% in neuron numbers in the CA1 subfield, while numbers in the other subfields were unchanged. There was a corresponding significant reduction of 22% in the volume of the CA1 subfield and a significant 14% decrease in the volume of the pyramidal layer of the subiculum. The change in volume of the pyramidal layer of the subiculum without neuron loss may reflect loss of CA1 afferent input to the pyramidal layer. Although the effect of nutritional deprivation on the neuronal population appears to be different in pre- and postnatal malnutrition, both dietary paradigms highlight the vulnerability of key components of the hippocampal trisynaptic circuit (consisting of the dentate granule cell mossy fibers projection to CA3 pyramids and the CA3 projection to the CA1 pyramids), which is an essential circuit for memory and learning.

There is considerable evidence for lateralization of hippocampal function and hemispheric asymmetry in humans. In the rat, studies have reported asymmetries in the thicknesses of layers, the volumes of hippocampal subfields, and the density of cells at specific points along the septotemporal axis. To determine if there is an asymmetry of neuron numbers and whether prenatal malnutrition affects any asymmetries, 90-day old male Sprague-Dawley rats that were either normally nourished or malnourished prenatally were perfused with 4% paraformaldehyde and the brains cut into 30-micro m sections. One interrupted series of sections through the entire hippocampus was analyzed stereologically to estimate the total number of neurons in the hilus of the dentate gyrus, the CA3/CA2 stratum pyramidale (SP), the CA1 SP, and the SP of the prosubiculum/subiculum of both hemispheres. Significant asymmetries (P < 0.05) were found in the CA1 and CA3/CA2 subfields, with the right hemisphere containing 21 and 6% fewer neurons, respectively. Malnutrition reduced neuron numbers in the CA1 subfield by 12%, but did not alter the hemispheric asymmetry. Our findings agree with previous reports of left dominant asymmetries in the rat brain and suggest that this may result from differences in total numbers of neurons.

Object recognition memory requires the perirhinal cortex (PRC) and this cognitive function declines during normal aging. Recent electrophysiological recordings from young rats have shown that neurons in layer V of the PRC are activated by 3-dimensional objects. Thus, it is possible that age-related object recognition deficits result from alterations in PRC neuron activity in older animals. To examine this, the present study used cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH) with confocal microscopy to monitor cellular distributions of activity-induced Arc RNA in layer V of the PRC. Activity was monitored during two distinct epochs of object exploration. In one group of rats (6 young/6 aged) animals were placed in a familiar testing arena and allowed to explore five different 3-dimensional objects for two 5-min sessions separated by a 20-min rest (AA). The second group of animals (6 young/6 aged) also explored the same objects for two 5-min sessions, but the environment was changed between the first and the second epoch (AB). Behavioral data showed that both age groups spent less time exploring objects during the second epoch, even when the environment changed, indicating successful recognition. Although the proportion of active neurons between epochs did not change in the AA group, in the AB group more neurons were active during epoch 2 of object exploration. This recruitment of neurons into the active neural ensemble could serve to signal that familiar stimuli are being encountered in a new context. When numbers of Arc positive neurons were compared between age groups, the old rats had significantly lower proportions of Arc-positive PRC neurons in both the AA and AB behavioral conditions. These data support the hypothesis that age-associated functional alterations in the PRC contribute to declines in stimulus recognition over the lifespan.

The CA1 region of the hippocampus receives distinct patterns of afferent input to distal (near subiculum) and proximal (near CA2) zones. Specifically, distal CA1 receives a direct projection from cells in the lateral entorhinal cortex that are sensitive to objects, while proximal CA1 is innervated by cells in the medial entorhinal cortex that are responsive to space. This suggests neurons in different areas along the promixodistal axis of CA1 of the hippocampus will be functionally distinct. The current experiment investigated this possibility by monitoring behavior-induced cell activity across the CA1 axis using Arc mRNA imaging methods that compared adult and old rats in two conditions: exploration of the same environment containing the same objects twice (AA), or exploration of two different environments that contained identical objects (AB). The hypothesis was that CA1 place cells should show field remapping in the condition where environments were changed, but the extent of remapping was expected to differ between proximal and distal regions, and between age groups. In fact, neurons in the proximal region of CA1 in adult animals exhibited a greater degree of remapping than did distal CA1 cells when the environment changed, suggesting that cells receiving input from the medial entorhinal cortex are more sensitive to spatial context. In old rats, however, there were no differences in remapping across the proximodistal CA1 axis. Together these data suggest that distal and proximal CA1 may be functionally distinct and differentially vulnerable to normative aging processes.