Department of Anatomy and Neurobiology, Kindai University School of Medicine 377-2 Ohno-Higashi, Osakasayama City, Osaka, 589-8511, Japan.
Information Systems Center, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku Kitakyushu-shi, Fukuoka, 807-8555, Japan.
Sci Rep. 2018 Jan 16;8(1):854. doi: 10.1038/s41598-018-19224-1.
In mammals, the principal circadian oscillator exists in the hypothalamic suprachiasmatic nucleus (SCN). In the SCN, CLOCK works as an essential component of molecular circadian oscillation, and ClockΔ19 mutant mice show unique characteristics of circadian rhythms such as extended free running periods, amplitude attenuation, and high-magnitude phase-resetting responses. Here we investigated what modifications occur in the spatiotemporal organization of clock gene expression in the SCN of ClockΔ19 mutants. The cultured SCN, sampled from neonatal homozygous ClockΔ19 mice on an ICR strain comprising PERIOD2::LUCIFERASE, demonstrated that the Clock gene mutation not only extends the circadian period, but also affects the spatial phase and period distribution of circadian oscillations in the SCN. In addition, disruption of the synchronization among neurons markedly attenuated the amplitude of the circadian rhythm of individual oscillating neurons in the mutant SCN. Further, with numerical simulations based on the present studies, the findings suggested that, in the SCN of the ClockΔ19 mutant mice, stable oscillation was preserved by the interaction among oscillating neurons, and that the orderly phase and period distribution that makes a phase wave are dependent on the functionality of CLOCK.
在哺乳动物中，主要的生物钟振荡器存在于下丘脑视交叉上核（SCN）中。在 SCN 中，CLOCK 作为分子生物钟振荡的重要组成部分，ClockΔ19 突变小鼠表现出独特的生物钟节律特征，如自由运行周期延长、振幅衰减和高幅度相位重置反应。在这里，我们研究了 ClockΔ19 突变体 SCN 中时钟基因表达的时空组织发生了什么变化。从包含 PERIOD2::LUCIFERASE 的 ICR 品系的新生纯合子 ClockΔ19 小鼠中采集的培养 SCN 表明，Clock 基因突变不仅延长了生物钟周期，还影响了 SCN 中生物钟振荡的空间相位和周期分布。此外，神经元之间同步的破坏显著减弱了突变 SCN 中单个振荡神经元的昼夜节律振幅。此外，基于本研究的数值模拟结果表明，在 ClockΔ19 突变小鼠的 SCN 中，振荡神经元之间的相互作用保持了稳定的振荡，使相位波具有有序的相位和周期分布依赖于 CLOCK 的功能。
