Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging

Abstract

The hippocampal formation contains a distinct population of neurons organized into separate anatomical subregions. Each hippocampal subregion expresses a unique molecular profile accounting for their differential vulnerability to mechanisms of memory dysfunction. Nevertheless, it remains unclear which hippocampal subregion is most sensitive to the effects of advancing age. Here we investigate this question by using separate imaging techniques, each assessing different correlates of neuronal function. First, we used MRI to map cerebral blood volume, an established correlate of basal metabolism, in the hippocampal subregions of young and old rhesus monkeys. Second, we used in situ hybridization to map Arc expression in the hippocampal subregions of young and old rats. Arc is an immediate early gene that is activated in a behavior-dependent manner and is correlated with spike activity. Results show that the dentate gyrus is the hippocampal subregion most sensitive to the effects of advancing age, which together with prior studies establishes a cross-species consensus. This pattern isolates the locus of age-related hippocampal dysfunction and differentiates normal aging from Alzheimer's disease.

Fig. 1.

High-resolution images visualize individual hippocampal subregions. Maps of CBV were generated from T1-weighted images that possess high spatial and anatomical resolution. Images were acquired perpendicular to the hippocampal long axis, and the upper left image shows an example in which the hippocampal subregions can be visualized. The external morphology and the internal architecture of the hippocampus (white lines) are used as landmarks to segment the hippocampus into the subiculum (blue), the CA1 subfield (green), and the dentate gyrus (red). Note that border zones between the subiculum and CA1 subregion are excluded from analysis. The entorhinal cortex (yellow) is identified in more anterior images, as shown in the lower left image, relying on the underlying white matter and the collateral sulcus as anatomical landmarks.

Fig. 2.

CBV measured from the dentate gyrus differentially correlates with age in rhesus monkeys. (A) Individual examples of gadolinium-induced change in MRI signal, a measure of CBV and a correlate of brain metabolism, acquired from a young and old rhesus monkey. Warmer colors indicate higher CBV. The white circle, identified in precontrast images, overlies the dentate gyrus. (B) CBV measurements are plotted against age for individual hippocampal subregions. A significant age-related decline in CBV was observed only the dentate gyrus. (C) CBV measurements are plotted against memory performance on the delayed nonmatching-to-sample test. A significant relationship between CBV and memory was observed only in the dentate gyrus.

Fig. 3.

Arc expression in the granule cells of the dentate gyrus differentially correlates with age in rats. (A) Individual examples of behaviorally induced Arc RNA staining, a correlate of spike activity, in hippocampal granule cells of a young and an old rat. Red is the nuclear counterstain propidium iodide, and green is fluorescent-tagged (CY3) Arc RNA. (Scale bar, 20 μm.) (B) The average percent of Arc-positive neurons measured from the three different age groups (9, 15, and 24 months) are shown for individual hippocampal subregions. Note that there are significantly fewer Arc-positive granule cells in old rats compared with stability in the numbers of Arc-positive pyramidal cells. On average, older rats express Arc RNA in fewer cells than did young rats, and this significant age-related decline in Arc expression was observed only in the dentate gyrus.