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

摘要/摘要 运动活动、体温和荷尔蒙水平的异常昼夜节律不仅强烈 相关的许多神经退行性疾病，包括阿尔茨海默病(AD)在人类患者和 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中断。 本身会导致认知缺陷。目前也不清楚中央生物钟是否以及如何在 下丘脑的视交叉上核(SCN)参与认知功能。在这里我们发现了一个 AD小鼠模型(APP NL-G-F)显示破坏的SCN分子时钟，包括核受体Rev-erbα 和REV-ERBβ，这些分子缺陷会导致可检测到的认知功能障碍。昼夜节律紊乱， 无论是通过持续的光照暴露，还是通过SCN GABA能神经元中REV-ERB的基因缺失，导致 认知功能障碍类似于APP NL-G-F小鼠。我们假设打乱了生物钟 阿尔茨海默病患者的认知功能障碍与SCN及其起源的神经回路改变有关。我们会 确定SCN中REV-ERB的恢复是否能挽救APP NL-G-F小鼠的认知缺陷；确定 是否需要有节奏的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&GT；PVT回路是否调节认知功能。现代人类社会的特点是 有夜间照明、夜间进食、社交时差和倒班工作。这些昼夜节律的扰乱 与记忆缺陷和神经退行性疾病有关，特别是在老年人口中。建议数 这项研究结合了独特的遗传动物模型、光照时间表操纵、精确的神经调节工具，以及 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 为时间治疗干预奠定基础。

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.