Circadian clock gene Rev-erb in memory dysfunction in Alzheimer's disease

生物钟基因 Rev-erb 在阿尔茨海默病记忆功能障碍中的作用

• 批准号: 10095219
• 负责人: Zheng Sun
• 金额: $ 182.79万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10095219
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Genetics; Animal Model; Body Temperature; Brain region; Circadian Dysregulation; Circadian Rhythms; Cognitive; Cognitive deficits; Data; Exposure to; Functional disorder; Genetic; Genetic Models; Hormonal; Human; Hyperactivity; Hypothalamic structure; Impaired cognition; Intervention; Jet Lag Syndrome; Light; Memory; Memory Loss; Memory impairment; Methods; Modeling; Modernization; Molecular; Motor Activity; Mus; Neurodegenerative Disorders; Neurons; Nuclear Receptors; Patients; Pattern; Periodicity; Phase; Schedule; Signal Transduction; Societies; Structure of paraventricular nucleus of thalamus; Synapses; Testing; Tetanus Helper Peptide; Wild Type Mouse; aging population; circadian; circadian pacemaker; cognitive function; feeding; gamma-Aminobutyric Acid; insight; molecular clock; mouse model; neural circuit; neuroregulation; neurotransmission; novel; relating to nervous system; restoration; rev Genes; shift work; social; suprachiasmatic nucleus; tool

ABSTRACT/SUMMARY Abnormal circadian rhythms of locomotor activities, body temperature, and hormonal levels not only are strongly associated many neurodegenerative disorders including Alzheimer’s disease (AD) in both human patients and animal models, but also precede cognitive deficits. However, it is unclear whether and how circadian disruption per se causes cognitive deficits. It is also unclear whether and how the central circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus contributes to cognitive functions. Here we found that an AD mouse model (APP NL-G-F) displays disrupted SCN molecular clock, including nuclear receptors Rev-erbα and Rev-erbβ, and these molecular deficits proceed detectable cognitive dysfunctions. Circadian disruptions, either by constant light exposure or by genetic deletion of Rev-erb in the SCN GABAergic neurons, cause cognitive dysfunctions resembling those in APP NL-G-F mice. We hypothesize that disrupted circadian clock in the SCN and alterations in SCN-originated neural circuitry contributes to cognitive dysfunctions in AD. We will determine whether restoration of Rev-erb in the SCN rescues cognitive deficits in APP NL-G-F mice; determine whether rhythmic SCN GABA neuron firing pattern is required to maintain normal cognitive functions; and determine whether the GABA-SCN>PVT circuit regulates cognitive functions. Modern human society is featured with nighttime light, nighttime feeding, social jetlag, and shift work. These circadian disruptions are highly associated with memory deficits and neurodegenerative diseases, especially in aged populations. The proposed study combines unique genetic animal models, light schedule manipulation, precise neuromodulation tools, and cutting-edge molecular methods to address mechanisms of how circadian disruptions cause cognitive deficits. Accomplishing these aims will provide novel insights into the pathophysiology of AD-related dementia, and lay groundwork for chronotherapeutic interventions.

摘要/总结 运动活动、体温和激素水平的昼夜节律异常不仅强烈地影响着 与许多神经退行性疾病相关，包括人类患者中的阿尔茨海默病（AD）， 动物模型，但也先于认知缺陷。然而，目前还不清楚昼夜节律是否以及如何被破坏， 会导致认知缺陷目前还不清楚中枢生物钟是否以及如何在 下丘脑的视交叉上核（SCN）有助于认知功能。我们发现， AD小鼠模型（APP NL-G-F）显示SCN分子钟被破坏，包括核受体Rev-erbα 和Rev-erbβ，这些分子缺陷导致可检测的认知功能障碍。昼夜节律紊乱， 通过持续的光照或通过SCN GABA能神经元中Rev-erb的基因缺失， 认知功能障碍类似于APP NL-G-F小鼠中的那些。我们假设， SCN和SCN起源的神经回路的改变有助于AD中的认知功能障碍。我们将 确定SCN中Rev-erb的恢复是否挽救APP NL-G-F小鼠中的认知缺陷; 是否需要节律性SCN GABA神经元放电模式来维持正常的认知功能;以及 确定GABA-SCN>PVT回路是否调节认知功能。现代人类社会的特点是 夜间照明，夜间喂食，社会时差和轮班工作。这些昼夜节律的紊乱 与记忆缺陷和神经退行性疾病相关，特别是在老年人群中。拟议 这项研究结合了独特的遗传动物模型，轻度时间表操纵，精确的神经调节工具， 尖端的分子方法来解决昼夜节律紊乱如何导致认知缺陷的机制。 实现这些目标将为AD相关痴呆的病理生理学提供新的见解，并奠定基础。 为慢性病干预奠定基础。