Department of Physics, Korea University, Seoul, Korea.
University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS Comput Biol. 2022 Jun 6;18(6):e1010213. doi: 10.1371/journal.pcbi.1010213. eCollection 2022 Jun.
The biological master clock, suprachiasmatic nucleus (of rat and mouse), is composed of 10,000 clock cells which are heterogeneous with respect to their circadian periods. Despite this inhomogeneity, an intact SCN maintains a very good degree of circadian phase (time) coherence which is vital for sustaining various circadian rhythmic activities, and it is supposedly achieved by not just one but a few different cell-to-cell coupling mechanisms, among which action potential (AP)-mediated connectivity is known to be essential. But, due to technical difficulties and limitations in experiments, so far very little information is available about the morphology of the connectivity at a cellular scale. Building upon this limited amount of information, here we exhaustively and systematically explore a large pool (25,000) of various network morphologies to come up with some plausible network features of SCN networks. All candidates under consideration reflect an experimentally obtained 'indegree distribution' as well as a 'physical range distribution of afferent clock cells.' Then, importantly, with a set of multitude criteria based on the properties of SCN circadian phase waves in extrinsically perturbed as well as in their natural states, we select out appropriate model networks: Some important measures are, 1) level of phase dispersal and direction of wave propagation, 2) phase-resetting ability of the model networks subject to external circadian forcing, and 3) decay rate of perturbation induced "phase-singularities." The successful, realistic networks have several common features: 1) "indegree" and "outdegree" should have a positive correlation; 2) the cells in the SCN ventrolateral region (core) have a much larger total degree than that of the dorsal medial region (shell); 3) The number of intra-core edges is about 7.5 times that of intra-shell edges; and 4) the distance probability density function for the afferent connections fits well to a beta function. We believe that these newly identified network features would be a useful guide for future explorations on the very much unknown AP-mediated clock cell connectome within the SCN.
生物钟的生物主钟位于视交叉上核（大鼠和小鼠），由大约 10000 个时钟细胞组成，这些细胞在其昼夜节律周期上存在异质性。尽管存在这种异质性，但完整的 SCN 仍能保持非常好的昼夜相位（时间）相干性，这对于维持各种昼夜节律活动至关重要，这似乎不仅是通过一种，而是几种不同的细胞间耦合机制来实现的，其中动作电位（AP）介导的连接被认为是必不可少的。但是，由于实验中的技术困难和限制，到目前为止，关于细胞尺度上连接的形态学信息非常有限。在此基础上，我们利用有限的信息，系统地探索了一个大规模的（~25000 个）各种网络形态，以提出一些合理的 SCN 网络的网络特征。所有考虑的候选者都反映了实验获得的“入度分布”以及“传入时钟细胞的物理范围分布”。然后，重要的是，我们根据外在扰动以及自然状态下 SCN 昼夜节律相位波的特性，基于一组多种标准，选择出合适的模型网络：一些重要的措施包括，1）相位分散的程度和波传播的方向，2）模型网络对外界昼夜节律强迫的相位重置能力，以及 3）由外部诱发的“相位奇异”的衰减率。成功的现实网络具有几个共同特征：1）“入度”和“出度”应该呈正相关；2）SCN 腹外侧区域（核心）的细胞总度数比背内侧区域（壳）大得多；3）核心内的连接数大约是壳内连接数的 7.5 倍；4）传入连接的距离概率密度函数与β函数拟合良好。我们相信，这些新确定的网络特征将为未来在 SCN 内进行非常未知的 AP 介导的时钟细胞连接组学研究提供有用的指导。
