A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal.
A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal.
复制标题
DOI：
10.7554/elife.05105
复制
发表时间：
2014-12-29
期刊：
影响因子：
7.7
通讯作者：
Storch KF
中科院分区：
文献类型：
--
作者：
Blum ID;Zhu L;Moquin L;Kokoeva MV;Gratton A;Giros B;Storch KF
在哺乳动物物种中观察到不依赖于视交叉上核中的主昼夜节律起搏器的运动活动的超昼夜节律（~4小时），然而，驱动这些节律的潜在机制尚不清楚。我们发现，多巴胺转运蛋白基因的破坏会延长小鼠超电运动节律的周期。中脑多巴胺神经元的化学遗传学激活和精神兴奋剂治疗也会导致经期延长，而抗精神病药氟哌啶醇则具有相反的作用。我们进一步揭示，纹状体多巴胺水平与超电活动周期同步波动，并且多巴胺能音强烈预测超电周期。我们的数据表明，哺乳动物大脑中存在一种唤醒调节多巴胺能超电振荡器（DUO），其通常与生物钟和谐地循环，但当多巴胺张力升高时可能会失去同步，从而产生异常的唤醒模式，这与与精神病理学共存的扰动的睡眠-觉醒周期惊人地相似。 DOI：http://dx.doi.org/10.7554/eLife.05105.001 哺乳动物的睡眠-觉醒周期由大脑内的“生物钟”控制，该时钟与昼夜周期同步。然而，哺乳动物生理学的其他方面，包括警觉性和活动水平，以及食欲和体温，都会以每隔几个小时重复一次的周期波动。这些周期被称为超日节律，它们可以通过在群体成员之间协调潜在的危险行为（例如觅食）来提供生存益处。尽管它们具有广泛的性质，而且它们在进化中似乎是保守的，但实际上人们对超电节律的分子基础一无所知。布鲁姆等人。现在已经确定了大脑内的第二个内部时钟，他们将其命名为“DUO”，并表明该时钟通常与生物钟协同工作，以调节日常活动和警觉性模式。在小鼠身上进行的实验表明，DUO 使用大脑化学物质多巴胺大约每四个小时产生一次活动爆发。此外，当生物钟被破坏时，它仍然继续工作。对自由活动的小鼠进行的多巴胺测量表明，该化学物质的水平与动物的活动水平同步波动。此外，使大脑充满多巴胺的药物（例如甲基苯丙胺）会通过延长活动爆发之间的时间间隔来破坏 4 小时的周期，而阻断多巴胺受体的药物则具有相反的效果。除了揭示大脑协调每天重复多次的处理过程的机制之外，DUO 的识别还可以提供对精神疾病的生物学基础的见解。精神分裂症和双相情感障碍等疾病通常伴随着活动和休息模式的紊乱。虽然这些变化以前被归因于昼夜节律的破坏，但几乎没有直接证据证明这一点，这提出了这些变化可能反映了超昼夜节律的破坏的可能性。 DOI：http://dx.doi.org/10.7554/eLife.05105.002
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. DOI: http://dx.doi.org/10.7554/eLife.05105.001 The sleep-wake cycle of mammals is controlled by a ‘circadian clock’ within the brain, which is synchronized to the day–night cycle. However, other aspects of mammalian physiology including alertness and activity levels, as well as appetite and body temperature—fluctuate in cycles that repeat every few hours. These cycles are known as ultradian rhythms, and they may offer survival benefits by enabling potentially risky behaviors, such as foraging, to be coordinated between members of a group. Despite their widespread nature and the fact that they appear to be conserved in evolution, virtually nothing is known about the molecular basis of ultradian rhythms. Blum et al. have now identified a second internal clock within the brain, which they name ‘the DUO’, and shown that this clock normally works in concert with the circadian clock to regulate daily patterns of activity and alertness. Experiments in mice revealed that the DUO uses the brain chemical dopamine to generate bursts of activity roughly every four hours. Moreover, it continues to work when the circadian clock has been destroyed. Measurements of dopamine in freely moving mice showed that levels of the chemical fluctuate in synchrony with the animals' activity levels. Moreover, drugs that flood the brain with dopamine, such as methamphetamine, disrupt the 4-hour cycle by lengthening the period between bursts of activity, whereas drugs that block dopamine receptors have the opposite effect. As well as revealing a mechanism by which the brain coordinates processes that repeat several times per day, the identification of the DUO could also provide insights into the biological basis of psychiatric disorders. Conditions such as schizophrenia and bipolar disorder are often accompanied by disturbances in patterns of activity and rest. While these have previously been attributed to the disruption of circadian rhythms, there is little direct evidence for this, which raises the possibility that these changes might instead reflect the disruption of ultradian rhythms. DOI: http://dx.doi.org/10.7554/eLife.05105.002