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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=666050
• 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. **

昼夜节律起搏器的大师核核核核核核心入口处是光与黑暗的每日周期，在整个大脑和身体中传达了这些信息，以调节与外部环境同步的生理和行为过程。但是，明显的是，某些过程必须每天进行一次比一次更频繁，并且我们发现振荡器，振荡器通常在一个24小时内循环6次，这表明哺乳动物的大脑已经进化了机制以预测和/或驱动此类事件。我们称之为多巴胺能超级振荡器（DUO）的生物计时系统似乎特别驻留在多巴胺能细胞本身中，并驱动了唤醒的节奏。我们的初步数据表明，多巴胺是该振荡器的主要产出，但也决定了其周期。尽管二人组以约24个小时的速度与昼夜节律的振荡循环大约4个小时，但在高多巴胺色调下，它可以从昼夜节律计时器中分离，导致周期> 24小时。我们在表现出长期二人组的小鼠中看到的行为模式与与双极疾病和精神分裂症等心理病理学相关的异常日常活动模式相关。我们的发现导致了一个有趣的建议，即二人失调，而不是功能失调的昼夜节律会产生这些睡眠：唤醒周期疾病。 ****通过使用各种遗传和药理学，我们将针对和操纵多巴胺能系统，以既定位和解释这一新型节奏产生器的机械基础，但也是一个长期目标 - 确定其在精神障碍中的相关性。系统：昼夜节律。这项研究可能会表明，睡眠：与心理病理学相关的唤醒畸变，从注意力不足多动障碍到精神分裂症，与失调的长期二人组合有关。我们的研究还可能为开发基于行动学的生物标志物的开发铺平道路，以检测，监测和可能的心理病理学预测。最后，我们预计这些二人物可以被光和药物“统治”，但也可能是通过行为活动和食物来招募的。预测的洞察力可能会为治疗和预防基于多巴胺降低的精神疾病提供一种新颖而多方面的方法。 **