Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Pharmacol Biochem Behav. 2022 Jun;217:173388. doi: 10.1016/j.pbb.2022.173388. Epub 2022 Apr 18.
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.
随着人类平均寿命的延长，与年龄相关的认知能力下降和昼夜节律紊乱问题日益严重。多株衰老加速小鼠（SAM）的寿命缩短，尤其是 SAMP8 株，其行为认知缺陷和双相昼夜节律运动活动模式已得到充分证实。然而，关于这些品系小鼠海马体中昼夜节律调节的了解甚少。在这里，我们验证了一个假设，即在这个早期衰老模型中，SAMP8 动物分子生物钟的破坏会导致行为和生理的紊乱。尽管在这个年龄段，SAMP8 动物的轮跑活动节律已经紊乱，但我们发现 SAMP8 动物的 SCN 中 PER2 蛋白表达仍有正常的节律。有趣的是，尽管 SAMR1 对照动物的 PER2 表达有明显的 24 小时节律，但 SAMP8 动物的海马体中并没有观察到明显的 PER2 表达节律。我们还研究了限时喂养作为一种可能的策略来挽救紊乱的海马体可塑性。与 SAMR1 对照相比，限时喂养增加了 SAMP8 小鼠的 Schaffer 侧枝-CA1 突触的长时程增强（long-term potentiation，LTP）。总的来说，我们证实了这个早期衰老模型中昼夜节律运动节律的紊乱（早在 4 个月），并发现这种紊乱不是由于 SCN 中 PER2 水平的不规律；然而，其他的 SCN 外昼夜节律振荡器（如海马体）可能随着衰老加速而受损。
