Blum Ian D, Zhu Lei, Moquin Luc, Kokoeva Maia V, Gratton Alain, Giros Bruno, Storch Kai-Florian
Department of Psychiatry, McGill University, Montreal, Canada.
Douglas Mental Health University Institute, Montreal, Canada.
Elife. 2014 Dec 29;3:e05105. doi: 10.7554/eLife.05105.
Ultradian (~4 hr) rhythms in locomotor activity that do not depend on the master circadian pacemaker in the suprachiasmatic nucleus have been observed across mammalian species, however, the underlying mechanisms driving these rhythms are unknown. We show that disruption of the dopamine transporter gene lengthens the period of ultradian locomotor rhythms in mice. Period lengthening also results from chemogenetic activation of midbrain dopamine neurons and psychostimulant treatment, while the antipsychotic haloperidol has the opposite effect. We further reveal that striatal dopamine levels fluctuate in synchrony with ultradian activity cycles and that dopaminergic tone strongly predicts ultradian period. Our data indicate that an arousal regulating, dopaminergic ultradian oscillator (DUO) operates in the mammalian brain, which normally cycles in harmony with the circadian clock, but can desynchronize when dopamine tone is elevated, thereby producing aberrant patterns of arousal which are strikingly similar to perturbed sleep-wake cycles comorbid with psychopathology.
在哺乳动物中已观察到不依赖于视交叉上核主昼夜节律起搏器的超日节律（约4小时）的运动活动，但驱动这些节律的潜在机制尚不清楚。我们发现，多巴胺转运体基因的破坏会延长小鼠超日运动节律的周期。中脑多巴胺神经元的化学遗传激活和精神兴奋剂治疗也会导致周期延长，而抗精神病药物氟哌啶醇则有相反的效果。我们进一步揭示，纹状体多巴胺水平与超日活动周期同步波动，并且多巴胺能张力强烈预测超日周期。我们的数据表明，一种调节觉醒的多巴胺能超日振荡器（DUO）在哺乳动物大脑中起作用，它通常与生物钟协调循环，但当多巴胺张力升高时会不同步，从而产生与精神病理学共病的异常觉醒模式，这些模式与紊乱的睡眠-觉醒周期惊人地相似。
