Cognitive Deficits, Changes in Synaptic Function, and Brain Pathology in a Mouse Model of Normal Aging

Unchanged locomotor and rearing activity, but reduced percentage of activity in the center of the arena in aged mice. A, B, The total number of horizontal beam breaks (A) and rearings (B) are shown. No significant differences were detected between any of the age groups in either measure. C, The percentage of beam breaks that were recorded in the center of the locomotor arena is shown. Values are expressed as box plots, as defined in the Data analysis section of Materials and Methods. BB, Beam breaks. *p < 0.05, **p < 0.005.

Barnes maze performance is impaired in aged mice. A, B, Training sessions. The distance travelled (A) and velocity of movement (B) until the mice entered the escape tunnel during training are shown. C, D, Probe trials. C shows the number of exploration bouts that were recorded at the location of the target hole (defined as position 0) as well as each individual nontarget hole. The absolute value of the “hole number relative to the target” reflects the distance from the target hole. D, The average number of exploration bouts at the nontarget and target holes are shown. E, F, Reversal phase; the distance travelled (E) and the velocity of the movement (F) during the reversal phase of the task are shown. Values are expressed as the mean ± SEM (A–C, E, F) or box plots, as defined in the Data analysis section in Materials and Methods (D). *p < 0.05.

Contextual and cued fear conditioning training and testing are largely unaffected by age. A, The time course of freezing throughout the training is shown. Trial 1 and 2 refer to the first and second pairings of the NS or CS with the UCS. B, The time course of the motor responses in the training phase relative to the footshock is shown with a 2 s resolution using average values from the two trials. C, Percentage of freezing during the contextual FC test is shown. D, Percentage of freezing during the baseline and cued phase of the cued FC test is shown. Values are expressed as the mean ± SEM (A, B) or box plots, as defined in the Data analysis section in Materials and Methods (C, D). NS, Neutral stimuli.

Acoustic startle responses are reduced in aged mice. A, The movement intensity (artificial units) in response to 40 ms pulses of white noise (0–55 dB above background) is shown. B, The slope of the movement intensity over the stimulus intensity (in decibels above background) is shown. Values are expressed as the mean ± SEM (A) or box plots, as defined in the Data analysis section in Materials and Methods (B). ***p < 0.0001.

Active avoidance is impaired in aged mice in both multimodal and visual versions of the task. A, E, Percentage of successful avoidance trials is shown in blocks of 20 trials over the 2 day test period for the multimodal (A) and visual (E) version of the task. B, F, Slopes of the percentage of avoidance per trial are shown for the multimodal (B) and visual (F) AA task for both training days. C, D, G, H, The percentages of escapes (C, G) and escape failures (D, H) are shown in blocks of 20 trials over the 2 day test period for the multimodal (C, D) and visual (G, H) AA task. Values are expressed as the mean ± SEM (A, C, D, E, G, H) or box plots, as defined in the Data analysis section in Materials and Methods (B, F). *p < 0.05, **p < 0.005, ***p < 0.0001.

A–E, Active avoidance (A–D) and optokinetic testing (E) in an independent cohort. Visual active avoidance is mildly impaired in 19-month-old mice. A, The percentage of successful active avoidance trials is shown in blocks of 20 trials over the 2 day test period for the visual version of the task. B, Slopes of the percentage of avoidance per trial are shown for both AA training days. C, D, The percentages of escapes (C) and escape failures (D) are shown in blocks of 20 trials over the 2 day test period. E, Contrast sensitivity from optokinetic tests is shown across varying spatial frequencies (in c/d). Values are expressed as the mean ± SEM. SEMs are not visible in E since they range from only 0.014 to 0.092 across age groups and spatial frequencies. ^$p < 0.1, ***p < 0.0001.

Markers of gliosis (GFAP, CD68) are increased in aged mice. A, B, Examples of brain slices showing areas of GFAP-positive (A) and CD68-positive (B) staining in the HPF are shown from the NE condition. C, The percentage of the total tissue area that had clustered GFAP-positive staining is shown. D, The percentage of the total tissue area from the HPF that had enlarged CD68-positive staining is shown. Values are expressed as box plots, as defined in the Data analysis section in Materials and Methods. *p < 0.05, **p < 0.005, ***p < 0.0001.

c-Fos expression is reduced in the dentate gyrus, but not in the isocortex, of aged mice. A, Examples of brain slices showing the number of c-Fos-positive cells in the DG are shown from the NE condition. B, Aged mice had reduced c-Fos staining in the DG across environments when compared with young and middle-aged mice. C, In the isocortex, no age-dependent effects were observed. Values are expressed as box plots, as defined in the Data analysis section in Materials and Methods. **p < 0.005.