Age and Sex Influence Diurnal Memory Oscillations, Circadian Rhythmicity, and Per1 Expression

Background

The circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression.

Methods

We used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice.

Results

Young female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning- induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance.

Conclusions

This work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age.

Highlights

• Diurnal oscillations in spatial memory are sex- and age-dependent in mice

• Per1 learning-induced expression matches diurnal memory patterns

• Circadian rhythm patterns are sex- and age-dependent in mice

• Young females show good memory across the diurnal cycle

• Diurnal memory oscillations reemerge in old female mice

Plain language summary

Memory is an integral part of everyday functioning, and one that is known to decline with aging. Our lab has previously shown that the clock gene Period1 ( Per1) regulates spatial memory performance in young males, establishing a molecular link between circadian rhythms and memory. Young adult male mice show diurnal oscillations in memory consolidation, with the best memory occurring at midday, and the worst memory occurring at midnight. In the current study, we wanted to expand our work to young adult females, as well as an aged population of male and female mice. Using a simple spatial memory task, we measured diurnal changes in both memory performance and Per1 gene expression within the dorsal hippocampus (a brain region necessary for spatial memory). We found that old mice (both male and female) showed a correlation between high Per1 levels and better memory, as we have previously seen.

Conversely, young female mice performed well on the memory task at every timepoint but didn’t have a significant change in Per1 , indicating that they may be using some different mechanism to modulate memory performance. Finally, we used infrared activity monitoring to investigate several circadian rhythm related measures in young and old, male and female mice. We found that sex influenced the circadian rhythm more than age, and the group with the largest circadian disruption was aged males. Overall, this research provides new information about how both sex and age impact diurnal oscillations in both memory and activity, fundamental knowledge that has been lacking in the field.