Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus
Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus
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DOI：
10.1073/pnas.1511351113
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发表时间：
2016-03-29
影响因子：
11.1
通讯作者：
Hastings, Michael H.
中科院分区：
文献类型：
--
作者：
Smyllie, Nicola J.;Chesham, Johanna E.;Hastings, Michael H.
视交叉上核（SCN）是控制哺乳动物日常行为的主生物钟。它由一个异质的神经元网络组成，其中细胞自主的分子反馈回路决定了单个细胞的昼夜节律振荡的周期和幅度。相比之下，电路水平的一致性，同步性和合奏周期的属性是由细胞间的信号，并体现在一个昼夜节律波的基因表达，每天跨越SCN的进展。细胞自主和电路级机制如何在计时中相互作用还知之甚少。为了探索这种相互作用，我们使用交叉遗传学来创建时间嵌合小鼠，其中SCN含有多巴胺1a受体（Drd1a）细胞，其固有周期为24小时，而非Drd1a细胞具有20小时时钟。在体外SCN切片中记录体内昼夜节律行为以及细胞分子起搏表明，这种嵌合电路形成了稳健和弹性的昼夜节律钟。结果还表明，系综周期的计算是非线性的。此外，嵌合电路持续的基因表达波的nonchimeric SCN，表明这种电路水平的属性是独立的细胞内在周期的差异。24小时Drd 1a和20小时非Drd 1a神经元在设定系综周期中的相对优势可以通过暴露于共振或非共振24小时或20小时光照周期来切换。因此，嵌合电路揭示了电路级操作的意外原则，这些原则是SCN时钟的可塑性、弹性和鲁棒性的基础。在嵌合体小鼠中观察到的自发和光驱动的周期灵活性为SCN起搏细胞的概念提供了新的视角。
The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells.