Melatonin attenuates chronic sleep deprivation-induced cognitive deficits and HDAC3-Bmal1/clock interruption

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2023-09-18 DOI:10.1111/cns.14474

Yujie Hu, Yefan Lv, Xiaoyan Long, Guoshuai Yang, Jinxia Zhou

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Abstract

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Abstract Image

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褪黑素可减轻慢性睡眠剥夺引起的认知缺陷和HDAC3-Bmal1/时钟中断。

背景和目的：睡眠被认为是认知的关键调节因子，但其潜在机制却鲜为人知。在这项研究中，我们调查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紊乱的影响：方法：将36只Sprague-Dawley雄性大鼠分为三组：方法：将36只Sprague-Dawley雄性大鼠分为三组：生理盐水治疗的CRSD组、长期注射褪黑素（20 mg/kg/天）的CRSD组和非睡眠剥夺对照组。结果发现，CRSD显著降低了大鼠对新奇事物的识别指数：结果：CRSD明显降低了新物体定位的识别指数，增加了Morris水迷宫的逃逸潜伏期和行进距离，而褪黑素治疗减轻了CRSD引起的海马依赖性空间学习和记忆缺陷。此外，在海马和外周血中，脑和肌肉芳基烃受体核转运体样1（Bmal1）和昼夜节律运动输出周期（Clock）的mRNA在CRSD的作用下呈全局性下调，且具有恒定的内在振荡。海马Bmal1、Clock和HDAC3的蛋白水平在CRSD后也显著下调。褪黑激素治疗逆转了CRSD诱导的Bmal1/Clock和HDAC3在mRNA水平和蛋白质水平上的改变：我们的数据表明，褪黑激素治疗可通过调节 HDAC3-Bmal1/Clock 的相互作用减轻 CRSD 引起的认知障碍。这些发现拓宽了人们对睡眠与认知之间关系的理解，并为认知障碍提供了一个潜在的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.