Age-associated alterations of hippocampal place cells are subregion specific

Abstract

Aging is associated with spatial memory impairments and with deficient encoding of information by the hippocampus. In young adult rats, recent studies on the firing properties of hippocampal neurons have emphasized the importance of the CA3 subregion in the rapid encoding of new spatial information. Here, we compared the spatial firing patterns of CA1 and CA3 neurons in aged memory-impaired rats with those of young rats as they explored familiar and novel environments. We found that CA1 place cells in aged and young rats had similar firing characteristics in the familiar and novel environments. In contrast, aged CA3 place cells had higher firing rates in general and failed to change their firing rates and place fields as much as CA3 cells of young rats when the rats were introduced to a novel environment. Thus, aged CA3 cells failed to rapidly encode new spatial information compared with young CA3 cells. These data suggest an important and selective contribution of CA3 dysfunction to age-related memory impairment.

Figure 1.

Locations of the recording sites as determined by histology. Each site in which place cells were recorded with tetrodes is marked for young rats (black circles) and aged rats (gray triangles) in the hippocampus [adapted from Paxinos and Watson (1998)]. A, Recordings from bregma -2.5 mm. B, Recordings from bregma -3.3 mm. The arrow marks the site of the example section. C, Recordings from bregma -3.8 mm. D, An actual example of a histological section. The arrow marks the tetrode location that was marked with the Prussian blue reaction. cc, Corpus callosum; PoDG, polymorphic region of the dentate gyrus; DG, dentate gyrus; D3V, dorsal third ventricle; dhc, dorsal hippocampal commissure.

Figure 2.

Examples of young (A) and aged (B) CA1 place fields. The top row shows the experimental setup with the familiar (fam) environment and novel environment 1. The recording sites, the place fields, the tetrode waveforms, and the firing rate scale (in spikes per second) of two simultaneously recorded cells from each rat are shown. Note that the CA1 cells of both groups predominantly created new spatial representations, although firing rates (young cell 2) and even some subfields (aged cell 2) were often similar between the environments. cc, Corpus callosum; PoDG, polymorphic region of the dentate gyrus; DG, dentate gyrus; D3V, dorsal third ventricle; dhc, dorsal hippocampal commissure.

Figure 3.

Examples of young (A) and aged (B) CA3 place fields. The top row depicts the experimental setup with the familiar (fam) environment and novel environment 4. The recording sites, the place fields, the tetrode waveforms, and the firing rate scale (in spikes per second) of two simultaneously recorded cells from each rat are shown. Note that young CA3 cells created new spatial representations, and often some were active in only one environment (young cell 2). In contrast, the aged CA3 cells used similar place field representations for both environments and scarcely changed their firing rates. cc, Corpus callosum; PoDG, polymorphic region of the dentate gyrus; DG, dentate gyrus; D3V, dorsal third ventricle; dhc, dorsal hippocampal commissure.

Figure 4.

Examples of young (A) and aged (B) CA3 place fields. The top row depicts the experimental setup with the familiar (fam) environment and novel environment 2. The recording sites, the place fields, the tetrode waveforms, and the firing rate scale (in spikes per second) of two simultaneously recorded cells from each rat are shown. Note that young CA3 cells created new spatial representations, and often some were active in only one environment (young cell 1). In contrast, the aged CA3 cells used similar place field representations for both environments and scarcely changed their abnormally high firing rates. cc, Corpus callosum; PoDG, polymorphic region of the dentate gyrus; DG, dentate gyrus; D3V, dorsal third ventricle; dhc, dorsal hippocampal commissure.

Figure 5.

Aged CA3 cells have an abnormally high firing rate. The basic firing parameters of CA1 and CA3 place cells from young and aged rats are depicted in the familiar (fam) and novel environments. A, Overall firing rate. B, Maximum firing rate. C, Area of high firing rate. D, Spatial selectivity. Statistical significance, ^***p < 0.001 for comparison of aged CA3 cells to young CA3 cells. Error bars represent SEM.

Figure 6.

Comparison of firing rates of individual cells in the familiar and novel environments and in repeated trials in the familiar environment. A, Young cells in the familiar (trial 1) and novel environments. B, Aged cells in the familiar (trial 1) and novel environments. C, Young cells in the familiar1 (fam1) and familiar2 (fam2) trials. D, Aged cells in the familiar1 and familiar2 trials. Note that firing rates were well correlated for all comparisons, except for those of young CA3 cells between the familiar and new environments.

Figure 7.

Aged CA3 cells fail to rapidly encode changes in the environment. In three measures of how much the place cells changed their firing patterns in response to the novel environment, the aged CA3 cells changed much less than young CA3 cells. In contrast, in the control comparison between repeated trials in the familiar environment, there were no differences between the age groups. A, Overall firing rate change between the familiar and new environments. B, Maximum firing rate change between the familiar and new environments. C, Place field correlation between the familiar and new environments. D, Overall firing rate change between repeated trials in the familiar environment. E, Maximum firing rate change between repeated trials in the familiar environment. F, Place field correlation between repeated trials in the familiar environment. Statistical significance, ^***p < 0.001 for comparison of aged CA3 cells to young CA3 cells. fam1, Familiar1; fam2, familiar2. Error bars represent SEM.

Figure 8.

Changes in CA3 cells during the first and second sessions in the novel environment. Aged CA3 cells demonstrated less change than young CA3 cells during both sessions in the novel environment. Only CA3 cells are shown. A, Firing rate change. B, Maximum firing rate change. C, Place field similarity. Statistical significance, ^*p < 0.05 for comparison within aged CA3 of the first and second sessions. fam1, Familiar1; fam2, familiar2. Error bars represent SEM.

Figure 9.

Age-related changes to the hippocampal circuit. Dashed lines indicate a decrease with aging. Solid arrows remain intact. With aging, the entorhinal cortex provides less input to dentate gyrus and CA3, the medial septum provides less cholinergic modulation, interneuron activity is decreased, and the CA1 hippocampus is less excitable (depicted with a doubly insulated box). These changes may increase the activity of CA3 recurrent collaterals (in gray). EC, Entorhinal cortex; DG, dentate gyrus; int, interneurons; MS, medial septum; ACh, acetylcholine.