Circadian disruption of hippocampus in an early senescence male mouse model
Jennifer A Davis1, Jodi R Paul1, Mugdha V Mokashi1
1Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
Age-related cognitive decline and disruptions in circadian rhythms are growing problems as the average human life span increases. Multiple strains of the senescence-accelerated mouse (SAM) show reduced life span, and the SAMP8 strain in particular has been well documented to show cognitive deficits in behavior as well as a bimodal pattern of circadian locomotor activity. However, little is known about circadian regulation within the hippocampus of these strains of mice. Here we test the hypothesis that in this early senescence model, disruption of the molecular circadian clock in SAMP8 animals drives disrupted behavior and physiology. We found normal rhythms in PER2 protein expression in the SCN of SAMP8 animals at 4 months, despite the presence of disrupted wheel-running activity rhythms at this age. Interestingly, a significant rhythm in PER2 expression was not observed in the hippocampus of SAMP8 animals, despite a significant 24-h rhythm in SAMR1 controls. We also examined time-restricted feeding as a potential strategy to rescue disrupted hippocampal plasticity. Time-restricted feeding increased long-term potentiation at Schaffer collateral-CA1 synapses in SAMP8 mice (compared to SAMR1 controls). Overall, we confirm disrupted circadian locomotor rhythms in this early senescence model (as early as 4 months) and discovered that this disruption is not due to arrhythmic PER2 levels in the SCN; however, other extra-SCN circadian oscillators (i.e., hippocampus) are likely impaired with accelerated aging.
Insights
Accelerated aging in SAMP8 mice disrupts circadian rhythms, particularly in the hippocampus, not the SCN. Time-restricted feeding improved hippocampal plasticity, suggesting a potential intervention for age-related cognitive decline.
Area of Science:
- Neuroscience
- Chronobiology
- Aging Research
Background:
- Age-related cognitive decline and circadian rhythm disruptions are significant health concerns.
- The senescence-accelerated mouse prone 8 (SAMP8) strain exhibits cognitive deficits and altered activity patterns.
- Circadian regulation within the hippocampus of aging mice remains poorly understood.
Purpose of the Study:
- To investigate the hypothesis that molecular circadian clock disruption in the hippocampus contributes to behavioral and physiological changes in SAMP8 mice.
- To examine the role of PER2 protein expression in the suprachiasmatic nucleus (SCN) and hippocampus.
- To assess the efficacy of time-restricted feeding in ameliorating hippocampal plasticity deficits.
Main Methods:
- Assessment of PER2 protein expression rhythms in the SCN and hippocampus of SAMP8 and control SAMR1 mice.
- Monitoring of circadian locomotor activity patterns.
- Electrophysiological evaluation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses following time-restricted feeding.
Main Results:
- SAMP8 mice showed disrupted wheel-running activity rhythms at 4 months of age.
- Normal PER2 rhythms were observed in the SCN of SAMP8 mice, but not in their hippocampus.
- Significant hippocampal PER2 rhythms were present in control SAMR1 mice.
- Time-restricted feeding enhanced hippocampal LTP in SAMP8 mice compared to controls.
Conclusions:
- Circadian locomotor activity disruptions in the SAMP8 model are not solely due to arrhythmic PER2 expression in the SCN.
- Extra-SCN circadian oscillators, such as the hippocampus, are likely impaired in this early senescence model.
- Time-restricted feeding may be a viable strategy to rescue disrupted hippocampal plasticity and potentially mitigate age-related cognitive impairments.
