Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China.
CNS Neurosci Ther. 2024 Mar;30(3):e14474. doi: 10.1111/cns.14474. Epub 2023 Sep 18.
Sleep is predicted as a key modulator of cognition, but the underlying mechanisms are poorly understood. In this study, we investigated the effects of melatonin on chronic rapid eye movement sleep deprivation (CRSD)-induced cognitive impairment and circadian dysfunction in rat models.
Thirty-six Sprague-Dawley male rats were divided into three groups: CRSD with saline treatment, CRSD with chronic melatonin injection (20 mg/kg/day), and non-sleep-deprived control. The cognitive behavioral tests as well as the expression of clocks and HDAC3 were evaluated in all groups.
CRSD significantly reduced recognition index in novel object location, increased escape latency and distance traveling in Morris water maze while melatonin treatment attenuated CRSD-induced hippocampal-dependent spatial learning and memory deficits. Furthermore, the mRNAs of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1(Bmal1) and circadian locomotor output cycles kaput (Clock) were globally down-regulated by CRSD with constant intrinsic oscillation in both hippocampus and peripheral blood. The protein levels of hippocampal Bmal1, Clock, and HDAC3 were also remarkably down-regulated following CRSD. Melatonin treatment reversed CRSD-induced alterations of Bmal1/Clock and HDAC3 on both mRNA levels and protein levels.
Our data indicate that melatonin treatment attenuates CRSD-induced cognitive impairment via regulating HDAC3-Bmal1/Clock interaction. These findings explore a broader understanding of the relationship between sleep and cognition and provide a potential new therapeutic target for cognitive impairment.
睡眠被预测为认知的关键调节剂，但潜在机制尚不清楚。在这项研究中，我们研究了褪黑素对慢性快速眼动睡眠剥夺（CRSD）诱导的大鼠模型认知障碍和昼夜节律功能障碍的影响。
将 36 只雄性 Sprague-Dawley 大鼠分为三组：CRSD 生理盐水处理组、CRSD 慢性褪黑素注射（20mg/kg/天）组和非睡眠剥夺对照组。所有组均进行认知行为测试以及时钟和 HDAC3 的表达评估。
CRSD 显著降低了新物体位置识别指数，增加了 Morris 水迷宫中的逃避潜伏期和行驶距离，而褪黑素治疗减轻了 CRSD 诱导的海马依赖性空间学习和记忆缺陷。此外，CRSD 导致大脑和肌肉芳香烃受体核转位样蛋白 1（Bmal1）和昼夜节律运动输出周期 kaput（Clock）的 mRNAs 在海马体和外周血中均呈现固有振荡的情况下整体下调。海马体 Bmal1、Clock 和 HDAC3 的蛋白水平也随 CRSD 显著下调。褪黑素治疗逆转了 CRSD 诱导的 Bmal1/Clock 和 HDAC3 在 mRNA 水平和蛋白水平上的改变。
我们的数据表明，褪黑素治疗通过调节 HDAC3-Bmal1/Clock 相互作用减轻 CRSD 诱导的认知障碍。这些发现探索了睡眠与认知之间关系的更广泛理解，并为认知障碍提供了一个潜在的新治疗靶点。
