Two novel mouse models of slow-wave-sleep enhancement in aging and Alzheimer's disease.
Two novel mouse models of slow-wave-sleep enhancement in aging and Alzheimer's disease.
复制标题
衰老和阿尔茨海默氏病的两个新颖的小鼠模型，以增强慢波睡眠的增强。
DOI：
10.1093/sleepadvances/zpac022
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
衰老和阿尔茨海默病 (AD) 都与最深睡眠阶段（称为慢波睡眠 (SWS)）的数量和质量下降有关。慢波睡眠不足已被证明会使 AD 症状恶化并阻碍健康衰老。然而，由于缺乏可以专门操纵 SWS 的动物模型，人们对该机制仍然知之甚少。值得注意的是，最近在成年小鼠中开发了 SWS 增强的小鼠模型。作为评估 SWS 增强对衰老和神经退行性疾病影响的研究的前奏，我们首先询问是否可以在衰老和 AD 动物模型中增强 SWS。化学遗传受体 hM3Dq 在老年小鼠和 AD (APP/PS1) 小鼠模型面旁区的 GABA 能神经元中条件表达。在基线条件下以及氯氮平-N-氧化物（CNO）和媒介物注射后分析睡眠-觉醒表型。老年小鼠和 AD 小鼠均表现出睡眠质量缺陷，其特征是慢波活动减少。与媒介物注射相比，老年小鼠和 AD 小鼠在注射 CNO 后均表现出 SWS 增强，其特征是 SWS 潜伏期较短、SWS 数量和巩固增加以及慢波活动增强。重要的是，老年小鼠和 APP/PS1 模型小鼠中的 SWS 增强表型分别与成年和同窝野生型小鼠中观察到的相当。这些小鼠模型将首次使用 SWS 增益实验来研究 SWS 在衰老和 AD 中的作用。
Aging and Alzheimer’s disease (AD) are both associated with reduced quantity and quality of the deepest stage of sleep, called slow-wave-sleep (SWS). Slow-wave-sleep deficits have been shown to worsen AD symptoms and prevent healthy aging. However, the mechanism remains poorly understood due to the lack of animal models in which SWS can be specifically manipulated. Notably, a mouse model of SWS enhancement has been recently developed in adult mice. As a prelude to studies assessing the impact of SWS enhancement on aging and neurodegeneration, we first asked whether SWS can be enhanced in animal models of aging and AD. The chemogenetic receptor hM3Dq was conditionally expressed in GABAergic neurons of the parafacial zone of aged mice and AD (APP/PS1) mouse model. Sleep–wake phenotypes were analyzed in baseline condition and following clozapine-N-oxide (CNO) and vehicle injections. Both aged and AD mice display deficits in sleep quality, characterized by decreased slow wave activity. Both aged and AD mice show SWS enhancement following CNO injection, characterized by a shorter SWS latency, increased SWS amount and consolidation, and enhanced slow wave activity, compared with vehicle injection. Importantly, the SWS enhancement phenotypes in aged and APP/PS1 model mice are comparable to those seen in adult and littermate wild-type mice, respectively. These mouse models will allow investigation of the role of SWS in aging and AD, using, for the first time, gain-of SWS experiments.