Cognitive changes and circadian timekeeping disturbances in aging

Abstract

AbstractBackgroundCognitive changes in aging and Alzheimer’s disease (AD) are often accompanied by pronounced disturbances of circadian timekeeping, especially sleep‐wake cycle. Normal circadian timekeeping has an important impact on human health and performance by providing the temporal coordination of internal processes to insure their occurrence at the “right time” relative to each other and to the external environment. Aging of the rodent circadian system is characterized by changes comparable to those in human aging and AD. Common disturbances in the sleep‐wake rhythms of aged rodents include alterations in the light‐dark entrainment of this circadian rhythm. However, not all aged rodents show these changes, demonstrating the variability characteristic of human aging in pre‐dementia. The aging population also shows variability in onset and magnitude of cognitive impairment, but the relationship between these deficits with circadian rhythm disturbances has not yet been identified.MethodInitially, we tested young (3‐5 mon) and aged (18‐24 mon) C57Bl6 mice on wheel running activity continuously for 30‐40 days for circadian rhythm of locomotor activity. We then assessed learning and memory in the same mice using the Barnes maze task. Next, we wanted to determine if behavioral deficits occurred earlier in the lifespan (middle age) and whether changes in circadian activity occur prior to cognitive impairment.ResultAged mice were significantly impaired in all measures of activity rhythm entrainment and cognition. Interestingly, we observed a gender‐specific relationship between cognitive impairment in the Barnes maze and activity onset in aged female mice (20‐24 mon). Changes in activity rhythm entrainment were observed as early as 12‐14 months in middle aged mice. We also tested these mice for cognition (Barnes maze, novel and spatial recognition tests, 3 chamber sociability test) and motor behavior (rotarod, open field and digigait).ConclusionThis data will be the foundation of our model to further understand the relationship between circadian synchronization and age‐related cognitive impairment, and to probe possible mechanisms of action.