The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets.

中文翻译：

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视交叉上核神经元活动的星形细胞调节：数学模型的见解。

下丘脑的视交叉上核（SCN）由高度异质的神经元群组成，这些神经元群联网在一起，以允许哺乳动物精确而强大的昼夜节律计时。虽然 SCN 神经元在调节昼夜节律中的至关重要性已得到广泛研究，但 SCN 星形胶质细胞在昼夜节律系统功能中的作用尚不清楚。最近的实验表明，SCN 星形胶质细胞是昼夜节律振荡器，具有与 SCN 神经元相同的功能时钟基因。星形胶质细胞产生节律性输出，被认为通过突触前和突触后相互作用调节神经元活动。在这项研究中，我们开发了 SCN 时钟的计算机多细胞模型，以研究星形胶质细胞在调节神经元活动和影响关键时钟特性（如昼夜节律、周期和同步）方面的影响。该模型预测星形胶质细胞可以通过三方突触的双向相互作用改变神经元的节律活动。具体来说，星形胶质细胞调节的细胞外谷氨酸预计会增加神经元的神经肽信号传导。与实验结果一致，我们发现星形胶质细胞可以根据其内源性昼夜节律周期增加昼夜节律周期并增强神经同步。当星形胶质细胞的周期比神经元长 0 到 2 小时时，星形胶质细胞对昼夜节律幅度、周期和同步性的调节影响预计最强。增加与星形胶质细胞耦合的神经元数量也增加了其对周期调制和同步性的影响。这些计算结果表明，调节星形胶质细胞节律或信号传导（例如，作为季节、年龄或治疗的函数）的信号可能会导致昼夜节律紊乱或作为假定的治疗目标。