Development of an age-dependent cognitive index: relationship between impaired learning and disturbances in circadian timekeeping

Preclinical quantitative models of cognitive performance are necessary for translation from basic research to clinical studies. In rodents, non-cognitive factors are a potential influence on testing outcome and high variability in behavior requires multiple time point testing for better assessment of performance in more sophisticated tests. Thus, these models have limited translational value as most human cognitive tests characterize cognition using single digit scales to distinguish between impaired and unimpaired function. To address these limitations, we developed a cognitive index for learning based on previously described scores for strategies used by mice to escape the Barnes maze. We compared the cognitive index and circadian patterns of light-dark entrainment in young (4–6 months), middle-aged (13–14 months), and aged (18–24 months) mice as cognitive changes during aging are often accompanied by pronounced changes in sleep-wake cycle. Following continuous analysis of circadian wheel-running activity (30–40 days), the same cohorts of mice were tested in the Barnes maze. Aged mice showed significant deficits in the learning and memory portions of the Barnes maze relative to young and middle-aged animals, and the cognitive index was positively correlated to the memory portion of the task (probe) in all groups. Significant age-related alterations in circadian entrainment of the activity rhythm were observed in the middle-aged and aged cohorts. In middle-aged mice, the delayed phase angle of entrainment and increased variability in the daily onsets of activity preceded learning and memory deficits observed in aged animals. Interestingly, learning-impaired mice were distinguished by a positive relationship between the extent of Barnes-related cognitive impairment and variability in daily onsets of circadian activity. While it is unclear whether changes in the sleep-wake cycle or other circadian rhythms play a role in cognitive impairment during aging, our results suggest that circadian rhythm perturbations or misalignment may nevertheless provide an early predictor of age-related cognitive decline.