Cognitive trajectories in longitudinally trained 3xTg-AD mice

Abstract

Preclinical studies in Alzheimer's disease (AD) often rely on cognitively naïve animal models in cross-sectional designs that can fail to reflect the cognitive exposures across the lifespan and heterogeneous neurobehavioral features observed in humans. To determine whether longitudinal cognitive training may affect cognitive capacities in a well-characterized AD mouse model, 3xTg and wild-type mice (n = 20) were exposed daily to a training variant of the Go-No-Go (GNG) operant task from 3 to 9 months old. At 3, 6, and 9 months, performance on a testing variant of the GNG task and anxiety-like behaviors were measured, while long-term recognition memory was also assessed at 9 months. In general, GNG training improved performance with increasing age across genotypes. At 3 months old, 3xTg mice showed slight deficits in inhibitory control that were accompanied by minor improvements in signal detection and decreased anxiety-like behavior, but these differences did not persist at 6 and 9 months old. At 9 months old, 3xTg mice displayed minor deficits in signal detection, and long-term recognition memory capacity was comparable with wild-type subjects. Our findings indicate that longitudinal cognitive training can render 3xTg mice with cognitive capacities that are on par with their wild-type counterparts, potentially reflecting functional compensation in subjects harboring AD genetic mutations.

Keywords: 3xTg; Alzheimer's disease; Cognitive training; Go-No-Go; Resilience.

Figure 1.

Overview of study design. After initial autoshaping and pretraining, 3xTg and wild-type mice were trained to criterion on the 50:50 variant of the Go-No-Go (GNG) task at 3 months old, followed by testing on the 80:20 variant of the task across three consecutive testing days. Testing performance was also measured at 6 and 9 months old, while daily training on the 50:50 variant continued in-between these time points. After GNG testing at each time point, behavior in an elevated plus maze (EPM) was collected, and long-term memory (24 hr.) was also measured in a Novel Object Recognition (NOR) task at 9 months. ^A The 50:50 variant of the Go-No-Go task presented equal distributions of “Go” and “No-Go” trials. ^B The 20:80 variant of the Go-No-Go task presented 20% and 80% of trials as “Go” and “No-Go”, respectively. ^C Immunoblotting on a subset of brain tissues (hippocampus) was used to confirm the presence and absence of Aβ oligomers in 3xTg and wild type mice, respectively. Lysates from 3xTg subjects show the presence of a 64kDa band that corresponds to high molecular weight Aβ oligomers.

Figure 2.

Performance on the training variant (50:50) of the Go-No-Go (GNG) task. A) The number of training sessions to attain criterion on the GNG task did not differ between genotypes. B) Improvements in hit percentages were not statistically significant across ages or across genotype. C) Decreased false alarm percentages were significantly reduced across ages independent of genotype. D) Improvements in sensitivity index scores were statistically significant across ages independent of genotype. Differences in performance across ages as a function of genotype were assessed with mixed-model analyses of variance, and one-way analyses of variance were used to directly compare genotypes at each age. *p < .05; **p < .01.

Figure 3.

Performance on the testing variant (20:80) of the Go-No-Go (GNG) task. A) Percentages of testing day 1 false alarms across ages were significantly modified by genotype, primarily driven by significantly higher rates among 3xTg mice at 3 months old. Genotype interactions were not detected across other testing day 1 measures, although we did detect a significant decrease in B) hit percentages and C) sensitivity index scores among 3xTg mice at 9 months old. D) Genotype interactions were not detected on testing day 2 false alarm percentages, but E) hit percentages and F) sensitivity index scores across ages were significantly modified by genotype, primarily driven by significantly higher values among 3xTg mice at 3 months old. G) Genotype interactions were not detected on testing day 3 false alarm percentages. H) Percentages of testing day 3 hits were significantly modified by genotype, primarily driven by significantly higher and lower rates among 3xTg mice at 3 and 9 months old, respectively. I) Testing day 3 sensitivity scores were significantly modified by genotype, primarily driven by significantly lower values at 9 months old. Differences in performance across ages as a function of genotype were assessed with mixed-model analyses of variance, and one-way analyses of variance were used to directly compare genotypes at each age. *p < .05; **p < .01.

Figure 4.

Performance in the elevated plus maze (EPM). A) Time in open arms (% relative to time in closed arms) and B) time in open arms (% relative to total time) across ages were significantly modified genotype, with significantly higher times in open arms at 3 months old among 3xTg animals. Differences in performance across ages as a function of genotype were assessed with mixed-model analyses of variance, and one-way analyses of variance were used to directly compare genotypes at each age. *p < .05; **p < .01.

Figure 5.

Performance in the Novel Object Recognition (NOR) task. A) Absolute preference (time spent exploring the novel object minus the time exploring familiar object) was significantly higher among female mice. B) Relative preference (time exploring novel object relative to the total time exploring both objects) was not different between male and female subjects. One-way analyses of variance were used assess sex-differences in performance. *p < .05; **p < .01.