Modulation of basic biochemical and physiological processes by the circadian timing system is now recognized as a fundamental feature of all mammalian organ systems. Within the central nervous system, these clock-modulating effects are reflected in some of the most complex behavioral states including learning, memory, and mood. How the clock shapes these behavioral processes is only now beginning to be realized. In this review we describe recent findings regarding the complex set of cellular signaling events, including kinase pathways, gene networks, and synaptic circuits that are under the influence of the clock timing system and how this, in turn, shapes cognitive capacity over the circadian cycle. Further, we discuss the functional roles of the master circadian clock located in the suprachiasmatic nucleus, and peripheral oscillator populations within cortical and limbic circuits, in the gating of synaptic plasticity and memory over the circadian cycle. These findings are then used as the basis to discuss the connection between clock dysregulation and cognitive impairments resulting from Alzheimer’s disease (AD). In addition, we discuss the conceptually novel idea that in AD, there is a selective disruption of circadian timing within cortical and limbic circuits, and that it is the disruption/desynchronization of these regions from the phase-entraining effects of the SCN that underlies aspects of the early- and mid-stage cognitive deficits in AD. Further, we discuss the prospect that the disruption of circadian timing in AD could produce a self-reinforcing feedback loop, where disruption of timing accelerates AD pathogenesis (e.g., amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system. Lastly, we address potential therapeutic approaches that could be used to strengthen cellular timing networks and, in turn, how these approaches could be used to improve cognitive capacity in Alzheimer’s patients.

中文翻译：

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昼夜节律时钟、认知和阿尔茨海默氏病：突触机制、信号传导效应器和时间疗法


昼夜节律计时系统对基本生化和生理过程的调节现在被认为是所有哺乳动物器官系统的基本特征。在中枢神经系统内，这些时钟调节效应反映在一些最复杂的行为状态中，包括学习、记忆和情绪。时钟如何塑造这些行为过程现在才刚刚开始被人们认识到。在这篇综述中，我们描述了关于一系列复杂的细胞信号事件的最新发现，包括受时钟计时系统影响的激酶途径、基因网络和突触回路，以及这反过来如何塑造昼夜节律周期的认知能力。此外，我们讨论了位于视交叉上核的主生物钟以及皮质和边缘回路内的外周振荡器群体在昼夜节律周期中突触可塑性和记忆的门控中的功能作用。然后将这些发现用作讨论生物钟失调与阿尔茨海默病 (AD) 引起的认知障碍之间关系的基础。此外，我们还讨论了概念上新颖的想法，即在 AD 中，皮质和边缘回路内的昼夜节律计时存在选择性中断，并且这些区域因 SCN 的相位夹带效应而受到破坏/去同步化，这是各个方面的基础AD 早期和中期认知缺陷的研究。此外，我们还讨论了这样的前景：AD 中昼夜节律的破坏可能会产生一个自我强化的反馈循环，其中时间的破坏会加速 AD 的发病机制（例如淀粉样蛋白沉积、氧化应激和细胞死亡），进而导致进一步的破坏昼夜节律计时系统。 最后，我们讨论了可用于加强细胞计时网络的潜在治疗方法，以及如何使用这些方法来提高阿尔茨海默病患者的认知能力。