Characterization of a dopaminergic ultradian oscillator regulating arousal

多巴胺能超电振荡器调节唤醒的表征

• 批准号: RGPIN-2015-04034
• 负责人: Storch, KaiFlorian
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682149
• 关键词: Characterization; dopaminergic; ultradian; oscillator; regulating

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. **

视交叉上核内的主要昼夜节律起搏器带动每日的光明和黑暗周期，将这些信息传递到整个大脑和身体，以与外部环境同步调节生理和行为过程。然而，显然有可能某些过程发生的频率必须超过每天一次，而我们对振荡器的发现（通常在 24 小时内循环 6 次）表明哺乳动物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电振荡器（DUO），似乎专门存在于多巴胺能细胞本身内，并驱动唤醒节律。我们的初步数据表明，多巴胺是该振荡器的主要输出，但也决定了其周期。虽然 DUO 似乎以大约 4 小时的周期循环，与生物钟的 ~24 振荡同步，但它可以在高多巴胺音调下与昼夜节律计时器分离，导致周期 >24 小时。我们在表现出长期 DUO 的小鼠中看到的行为模式与与躁郁症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，我们的研究结果得出了一个有趣的建议，即失调的 DUO 而不是功能失调的昼夜节律计时器产生了这些睡眠：觉醒周期干扰。***拟议的研究计划旨在进一步表征这种新型振荡器，它似乎存在于多巴胺能系统内，并且严重依赖多巴胺能音调，与众所周知的昼夜节律系统并行控制节律过程。*** 利用各种遗传和药理学，我们将瞄准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，同时作为长期目标，确定其与精神障碍病因学的相关性。***拟议的研究与我们最近的发现一起很可能会证明，每日的唤醒模式主要受两个振荡系统的调节：昼夜节律和节律节律。 亚电。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学相关的睡眠：觉醒周期异常与失调的长周期 DUO 相关。我们的研究还可能为开发基于体动记录仪的生物标记物铺平道路，用于检测、监测，甚至预测精神病理学。最后，我们预计 DUO 可以被光和药物所夹带或“控制”，但也可能被行为活动和食物所吸引或“控制”。预测的见解可能会为治疗和预防基于多巴胺失调的精神疾病提供一种新颖且多方面的方法。 **