Characterization of a dopaminergic ultradian oscillator regulating arousal

视交叉上核内的主要昼夜节律起搏器参与每日的光和暗循环，将这一信息传递到整个大脑和身体，以与外部环境同步地调节生理和行为过程。然而，很明显，某些过程必须比每天发生一次更频繁，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分子振荡器(DUO)，似乎专门驻留在多巴胺能细胞本身，并驱动觉醒的节奏。我们的初步数据表明，多巴胺是这种振荡器的主要输出，但也决定了它的周期。虽然二人组似乎以大约4小时的周期与生物钟的~24振荡同步，但在高多巴胺音调下，它可以与昼夜节律定时器分离，导致周期&gt；24小时。我们在表现出长时间二人组的小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疾病相关的异常日常活动模式惊人地一致。因此，我们的发现导致了一个有趣的假设，即调节失调的二人组而不是功能失调的昼夜节律计时器产生了这些睡眠：唤醒周期干扰。*拟议的研究计划旨在进一步描述这种新型振荡器的特征，这种振荡器似乎位于多巴胺能系统中，严重依赖多巴胺能音，与众所周知的昼夜节律系统并行地控制节律过程。*通过使用各种遗传和药理学方法，我们将针对和操纵多巴胺能系统，以定位和破译这种新的节律发生器的机制基础，并作为一个长期目标，确定其在精神障碍病因中的相关性。*拟议的研究与我们最新的发现很可能将证明，每天的唤醒模式主要由两个振荡系统调节：昼夜节律和超常规。这项研究可能进一步揭示，与从注意力缺陷多动障碍到精神分裂症等精神病理有关的睡眠：觉醒周期异常与调节失调的长期二人组有关。我们的研究也可能为基于动作学的生物标记物的发展铺平道路，用于检测、监测甚至预测精神病理学。最后，我们可以预计，这两个人可能会被光和药物缠住或“统治”，但也可能受到行为活动和食物的影响。预测的洞察力可能会为治疗和预防基于多巴胺调节障碍的精神疾病提供一种新的、多方面的方法。

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. **