Pendergast Julie S, Niswender Kevin D, Yamazaki Shin
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
VA Tennessee Valley Healthcare System, Nashville, TN, USA.
Eur J Neurosci. 2013 Oct;38(7):3044-53. doi: 10.1111/ejn.12309. Epub 2013 Jul 22.
The methamphetamine-sensitive circadian oscillator (MASCO) is an enigmatic circadian clock whose output is observed during continuous consumption of low-dose methamphetamine. The MASCO rhythm persists when the light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) is lesioned, but the anatomical location of MASCO is unknown. We recently found that the period of the MASCO rhythm is unusually short (21 h) in mice with disruption of all three paralogs of the canonical clock gene, Period. In this study, we investigated the contribution of each Period paralog to timekeeping in MASCO. We measured wheel-running activity rhythms in intact and SCN-lesioned Per1-, 2- and 3-mutant mice administered methamphetamine, and found that none of the mice displayed a short (21-h) period, demonstrating that no single Period gene is responsible for the short-period MASCO rhythm of Per1(-/-) /Per2(-/-) /Per3(-/-) mice. We also found that the periods of activity rhythms in constant darkness were lengthened by methamphetamine treatment in intact wild-type, Per1(-/-) and Per3(-/-) mice but not Per2(-/-) mice, and Per2(-/-) mice had two distinct activity rhythms upon release to constant light. These data suggest that the SCN and MASCO are not coupled in Per2(-/-) mice. The MASCO rhythm in Per1(-/-) /Per2(-/-) mice in constant darkness alternated between a short (22-h) and a long (27-h) period. This pattern could result from two coupled oscillators that are not synchronised to each other, or from a single oscillator displaying birhythmicity. Finally, we propose a working model of the in vivo relationship between MASCO and the SCN that poses testable hypotheses for future studies.
甲基苯丙胺敏感昼夜节律振荡器（MASCO）是一种神秘的昼夜节律时钟，其输出在持续摄入低剂量甲基苯丙胺期间可被观察到。当视交叉上核（SCN）中可被光调节的起搏器受损时，MASCO节律仍会持续，但MASCO的解剖位置尚不清楚。我们最近发现，在所有三个经典时钟基因Period的旁系同源基因均被破坏的小鼠中，MASCO节律的周期异常短（21小时）。在本研究中，我们调查了每个Period旁系同源基因在MASCO计时中的作用。我们测量了完整和SCN损伤的Per1、Per2和Per3突变小鼠在给予甲基苯丙胺后的转轮活动节律，发现没有一只小鼠表现出短（21小时）周期，这表明没有单个Period基因对Per1(-/-)/Per2(-/-)/Per3(-/-)小鼠的短周期MASCO节律负责。我们还发现，在持续黑暗中，完整的野生型、Per1(-/-)和Per3(-/-)小鼠的活动节律周期在甲基苯丙胺处理后延长，但Per2(-/-)小鼠没有，并且Per2(-/-)小鼠在释放到持续光照后有两种不同的活动节律。这些数据表明，在Per2(-/-)小鼠中，SCN和MASCO没有耦合。在持续黑暗中，Per1(-/-)/Per2(-/-)小鼠的MASCO节律在短（22小时）和长（27小时）周期之间交替。这种模式可能是由两个未相互同步的耦合振荡器导致的，或者是由一个显示双节律性的单个振荡器导致的。最后，我们提出了一个MASCO与SCN体内关系的工作模型，为未来的研究提出了可检验的假设。
