Characterization of a dopaminergic ultradian oscillator regulating arousal

视交叉上核内的主昼夜节律起搏器参与每日的光和暗循环，将此信息传达到整个大脑和身体，以调节与外部环境同步的生理和行为过程。然而，很明显，某些过程必须每天发生一次以上，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预测和/或驱动此类事件的机制。这种生物计时系统，我们称之为多巴胺能超日振荡器（DUO），似乎专门存在于多巴胺能细胞本身，并驱动唤醒的节奏。我们的初步数据表明，多巴胺作为这个振荡器的主要输出，但也决定了它的周期。虽然DUO似乎与昼夜节律钟的~24振荡同步地以约4小时的周期循环，但在高多巴胺水平下，它可以与昼夜节律计时器分离，导致周期> 24小时。我们在表现出长时间DUO的小鼠中看到的行为模式与与精神病理学（如双相情感障碍和精神分裂症）相关的异常日常活动模式惊人地一致。因此，我们的研究结果导致了一个有趣的建议，即DUO失调，而不是功能失调的昼夜节律计时器产生这些睡眠：唤醒周期紊乱。拟议的研究计划旨在进一步表征这种新的振荡器，它似乎位于多巴胺能系统内，并严重依赖于多巴胺能音调，与众所周知的昼夜节律系统平行地控制节奏过程。通过使用各种遗传学和药理学，我们将靶向和操纵多巴胺能系统，以便定位和破译这种新型节律发生器的机制基础，而且作为长期目标，确定其在精神障碍病因学中的相关性。很可能，拟议中的研究加上我们最近的发现将证明，日常唤醒模式主要由两个振荡系统调节：昼夜节律和超昼夜节律。这项研究可能进一步揭示，与精神病理学相关的睡眠：觉醒周期畸变，从注意缺陷多动障碍到精神分裂症，与失调的长期DUO相关。我们的研究也可能为开发一种基于活动记录的生物标志物铺平道路，用于检测，监测，甚至预测精神病理学。最后，我们预计DUO可以被光线和药物所携带或“统治”，但也可能被行为活动和食物所携带。预测的见解可能会提供一个新的和多方面的方法来治疗和预防多巴胺失调为基础的精神疾病。**

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. **