Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.
Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Transl Psychiatry. 2022 Aug 31;12(1):355. doi: 10.1038/s41398-022-02120-8.
Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called "clock genes/proteins", which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an "interaction triangle" model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).
生理和行为的昼夜节律（约 24 小时）是进化保守的，几乎存在于所有生物中。这些节律是由所谓的“时钟基因/蛋白”的每日振荡活动内在驱动的，这些基因/蛋白广泛分布于哺乳动物的大脑中。哺乳动物（机械）雷帕霉素靶蛋白（mTOR）信号是一种基本的细胞内信号转导级联，控制着包括神经发育、突触可塑性、代谢和衰老在内的重要神经元过程。mTOR 途径的失调与包括自闭症谱系障碍（ASD）和心境障碍（MD）在内的精神疾病有关，这些疾病患者经常表现出昼夜生理节律的破坏和大脑中异常的昼夜节律基因表达。最近的研究发现，mTOR 信号的活性受到生物钟的时间控制，并在多个系统中表现出强烈的昼夜振荡。同时，mTOR 信号调节中枢和外周生物钟的基本特性，包括周期长度、驯化和同步。尽管潜在的机制仍有待充分阐明，但越来越多的临床前和临床证据支持 mTOR 信号、生物钟和精神疾病之间存在显著的串扰。在这里，我们回顾了理解三方相互作用的最新进展，并提出了 mTOR 信号、生物钟和精神疾病（重点是 ASD 和 MD）之间的“相互作用三角”模型。
