Characterization of a dopaminergic ultradian oscillator regulating arousal

视交叉上核内的主昼夜节律起搏器携带着每天的光和暗循环，将这一信息传递到整个大脑和身体，与外部环境同步调节生理和行为过程。然而，很有可能的是，某些过程每天发生的频率一定不止一次，我们发现的振荡器通常在24小时内循环6次，这表明哺乳动物的大脑已经进化出了预测和/或驱动这些事件的机制。这种生物计时系统，我们称之为多巴胺能超频振荡器（DUO），似乎专门存在于多巴胺能细胞本身，并驱动觉醒的节奏。我们的初步数据表明，多巴胺是这个振荡器的主要输出，但也决定了它的周期。虽然DUO似乎以大约4小时的周期与昼夜节律时钟的~24振荡同步，但在高多巴胺音调下，它可以与昼夜节律计时器分离，导致周期为~24小时。我们在表现出长期DUO的老鼠身上看到的行为模式与与双相情感障碍和精神分裂症等精神病理学相关的异常日常活动模式惊人地一致。因此，我们的研究结果提出了一个有趣的建议，即是DUO失调，而不是昼夜节律计时器功能失调，导致了这些睡眠：觉醒周期紊乱。

The master circadian pacemaker within the suprachiasmatic nucleus entrains to daily cycles of light and darkness, conveying this information throughout the brain and body to modulate physiological and behavioural processes in synchrony with the external environment. It is distinctly possible, however, that certain processes must occur more frequently than once per day and our discovery of an oscillator, which typically cycles 6 times in a single 24 hour period suggests that the mammalian brain has evolved mechanisms to anticipate and/or drive such events. This biological timing system, which we have dubbed the dopaminergic ultradian oscillator (DUO), appears to reside specifically within dopaminergic cells themselves and drives rhythms of arousal. Our preliminary data suggests that dopamine acts as the principal output of this oscillator but also dictates its period. While the DUO seem to cycle with a period of about 4hrs in step with the ~24 oscillation of the circadian clock, it can dissociate from the circadian timer under high dopamine tone resulting in periods >24hr. The behavioural pattern we see in mice exhibiting a long-period DUO are in striking concordance to the abnormal daily activity patterns associated with psychopathologies such as bipolar disease and schizophrenia. Thus our findings lead to the intriguing suggestion that a dysregulated DUO and rather than a dysfunctional circadian timer produces these sleep:wake cycle disturbances. The proposed research program aims to further characterize this novel oscillator, which appears to reside within the dopaminergic system and critically relies on dopaminergic tone, governing rhythmic processes in parallel with the well-known circadian system. By using various genetic and pharmacological we will target and manipulate the dopaminergic system in order to both locate and decipher the mechanistic basis of this novel rhythm generator but also –as a long term goal- to determine its relevance in the etiology of mental disorders. It is likely that the proposed research together with our most recent findings will demonstrate that the daily patterns of arousal are chiefly regulated by two oscillatory systems: a circadian and an ultradian. This research may furthermore reveal that sleep:wake cycle aberrations associated with psychopathologies ranging from attention deficit hyperactivity disorder to schizophrenia are associated with a dysregulated, long-period DUO. Our studies may also pave the way for the development of an actigraphy-based biomarker for the detection, monitoring, and perhaps even prediction of psychopathologies. Finally, we anticipate that the DUO can be entrained or "reigned in" by light and drugs, but likely also by behavioral activity and food. The predicted insights will likely provide a novel and multi-facetted approach to the treatment and prevention of dopamine-dyregulation-based mental illnesses.