Astrocytes Sustain Circadian Oscillation and Bidirectionally Determine Circadian Period, But Do Not Regulate Circadian Phase in the Suprachiasmatic Nucleus.
Astrocytes Sustain Circadian Oscillation and Bidirectionally Determine Circadian Period, But Do Not Regulate Circadian Phase in the Suprachiasmatic Nucleus.
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DOI：
10.1523/jneurosci.2337-21.2022
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发表时间：
2022-07-13
影响因子：
5.3
通讯作者：
Hastings, Michael H.
中科院分区：
文献类型：
--
作者：
Patton, Andrew P.;Smyllie, Nicola J.;Chesham, Johanna E.;Hastings, Michael H.
视交叉上核（SCN）是哺乳动物的主生物钟，产生并传递环境时间的内部表征，该表征由10,000个神经元和3500个胶质细胞的细胞自主转录/翻译后反馈回路（ttfl）产生。最近，我们发现仅在SCN星形胶质细胞中TTFL功能就足以驱动昼夜节律计时和行为，这就提出了关于星形胶质细胞和神经元在SCN回路中各自贡献的问题。我们比较了它们在雌雄小鼠SCN外植体中昼夜节律计时的相对作用。用神经胶质特异性毒素氟柠檬酸盐治疗表明，需要具有代谢能力的星形胶质细胞来维持回路水平的时间。在cry1缺陷和/或cry2缺陷的scn中，利用重组酶介导的遗传互补隐色素（Cry）蛋白来比较神经元或星形胶质细胞的ttfl在新生振荡或起搏器启动中的影响。虽然神经元和星形胶质细胞都启动了新生振荡并同样延长了周期，但它们的动力学不同，星形胶质细胞的周期是前者的两倍。此外，星形胶质细胞可以缩短周期，但不如神经元有效。神经元中Gi-和gq偶联信号通路的化学发生操作分别急性提前或延迟集合期。相比之下，星形胶质细胞的类似操作没有效果。因此，星形胶质细胞可以启动SCN节律并双向控制SCN周期，尽管其效力低于神经元。然而，它们的激活并不影响SCN期。SCN高振幅振荡、节律性起始、起搏和相位的突发性特性受到不同的调控：星形胶质细胞和神经元维持持续的振荡，但其相位由神经元决定。下丘脑视交叉上核（SCN）编码和传播一天中的时间信息，使哺乳动物能够使其生理适应日常环境循环。最近的研究表明，除了神经元外，星形胶质细胞也参与了这种节律的调节。利用药理学、遗传互补和化学遗传学，我们比较了神经元和星形胶质细胞在决定高振幅振荡、节律性起始、起搏和相位确定等紧急SCN特性方面的能力。这些发现参数化了SCN中星形胶质细胞群体的昼夜节律特性，并揭示了星形胶质细胞和神经元在其异质细胞网络中可以贡献的昼夜节律信息类型。
The suprachiasmatic nucleus (SCN) is the master circadian clock of mammals, generating and transmitting an internal representation of environmental time that is produced by the cell-autonomous transcriptional/post-translational feedback loops (TTFLs) of the 10,000 neurons and 3500 glial cells. Recently, we showed that TTFL function in SCN astrocytes alone is sufficient to drive circadian timekeeping and behavior, raising questions about the respective contributions of astrocytes and neurons within the SCN circuit. We compared their relative roles in circadian timekeeping in mouse SCN explants, of either sex. Treatment with the glial-specific toxin fluorocitrate revealed a requirement for metabolically competent astrocytes for circuit-level timekeeping. Recombinase-mediated genetically complemented Cryptochrome (Cry) proteins in Cry1-deficient and/or Cry2-deficient SCNs were used to compare the influence of the TTFLs of neurons or astrocytes in the initiation of de novo oscillation or in pacemaking. While neurons and astrocytes both initiated de novo oscillation and lengthened the period equally, their kinetics were different, with astrocytes taking twice as long. Furthermore, astrocytes could shorten the period, but not as potently as neurons. Chemogenetic manipulation of Gi- and Gq-coupled signaling pathways in neurons acutely advanced or delayed the ensemble phase, respectively. In contrast, comparable manipulations in astrocytes were without effect. Thus, astrocytes can initiate SCN rhythms and bidirectionally control the SCN period, albeit with lower potency than neurons. Nevertheless, their activation does not influence the SCN phase. The emergent SCN properties of high-amplitude oscillation, initiation of rhythmicity, pacemaking, and phase are differentially regulated: astrocytes and neurons sustain the ongoing oscillation, but its phase is determined by neurons. SIGNIFICANCE STATEMENT The hypothalamic suprachiasmatic nucleus (SCN) encodes and disseminates time-of-day information to allow mammals to adapt their physiology to daily environmental cycles. Recent investigations have revealed a role for astrocytes, in addition to neurons, in the regulation of this rhythm. Using pharmacology, genetic complementation, and chemogenetics, we compared the abilities of neurons and astrocytes in determining the emergent SCN properties of high-amplitude oscillation, initiation of rhythmicity, pacemaking, and determination of phase. These findings parameterize the circadian properties of the astrocyte population in the SCN and reveal the types of circadian information that astrocytes and neurons can contribute within their heterogeneous cellular network.