The Role of Exercise in Controlling Central Mediators of Circadian Rhythm

运动在控制昼夜节律中枢调节因子中的作用

• 批准号: 10917632
• 负责人: Emily Elizabeth Schmitt
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10917632
• 关键词: Biology; Cancer Etiology; Cardiovascular Diseases; Centers of Research Excellence; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Coupling; Darkness; Disease; Exercise; Goals; Health; Human; International Agency for Research on Cancer; Light; Mediator; Metabolic syndrome; Modeling; Molecular; Mus; Neurons; Outcome; Pathway interactions; Pattern; Peripheral; Phase; Pilot Projects; Publishing; Qualifying; Reporting; Rodent Model; Role; Science; Sensory; Serotonin; Stroke; Testing; Work; Wyoming; circadian; circadian pacemaker; experimental study; molecular clock; neuropeptide Y; receptor; shift work; tool; transcriptome sequencing

Our overarching hypothesis is that chrono-timed exercise can restore rhythms in a misaligned central circadian clock. Despite the well-known benefits of exercise to overall health, limited studies have utilized exercise as a way to restore clock function, specifically in the SCN. Exercise can entrain peripheral clocks and elicit circadian phase-shifting effects but the underlying mechanisms are unknown. In particular, the coordinating efforts of the SCN in such exercise-induced entrainment of peripheral clocks is not fully known. It has recently been reported that mid-afternoon exercise in humans can phase-shift the peripheral molecular clock, yet more studies are needed to determine how exercise can be a chronobiological tool for alleviating circadian misalignment, specifically in the SCN. Our lab utilizes a well-published rodent model of circadian disruption. In addition, coupling my expertise of exercise science with our established model of circadian disruption uniquely qualifies our lab to study this aim. This proposal will implement a disruption of the light cycle to mimic chronic circadian disruption as seen in humans. Exercise will then be implemented to test if a normal rhythm can be restored. In this pilot study, we propose to test our central hypothesis that exercise during circadian disruption will re-align a disrupted central circadian clock through one specific aim comprised of two experiments. Our goal is to gain a better understanding of how exercise restores proper circadian function during circadian disruption. Our preliminary evidence suggests that chrono-timed exercise during circadian disruption via continual light-dark cycle phase shifts results in a pattern of Fos expression (a marker of neuronal activation) that more closely resembles undisrupted mice compared to mice that did not exercise. Here we will examine the relationship of this restored Fos pattern to markers of specific SCN input pathways that are known to be associated with exercise-induced entrainment, neuropeptide Y (NPY) and serotonin (5HT). We will also examine the molecular mediators underlying such modulation using RNA-seq, to determine whether the receptors for these pathways are upregulated.

我们的首要假设是，计时锻炼可以恢复失调的中央生物钟的节律。尽管运动对整体健康有众所周知的好处，但有限的研究利用运动作为恢复时钟功能的一种方法，特别是在视交叉上核中。运动可以带动外周时钟并引发昼夜节律相移效应，但其潜在机制尚不清楚。特别是，SCN 在这种运动引起的外周时钟夹带中的协调工作尚不完全清楚。最近有报道称，人类午后运动可以改变外周分子时钟的相移，但还需要更多的研究来确定运动如何成为缓解昼夜节律失调的时间生物学工具，特别是在视交叉上核中。我们的实验室利用了一种已发表的昼夜节律紊乱啮齿动物模型。此外，将我的运动科学专业知识与我们已建立的昼夜节律扰乱模型相结合，使我们的实验室有资格研究这一目标。该提案将扰乱光周期，以模仿人类的慢性昼夜节律紊乱。然后进行锻炼以测试是否可以恢复正常节律。在这项试点研究中，我们建议测试我们的中心假设，即昼夜节律紊乱期间的锻炼将通过由两个实验组成的一个特定目标来重新调整被扰乱的中央生物钟。我们的目标是更好地了解运动如何在昼夜节律紊乱期间恢复适当的昼夜节律功能。我们的初步证据表明，在昼夜节律中断期间，通过持续的明暗周期相移进行计时运动会导致 Fos 表达模式（神经元激活的标记），与不运动的小鼠相比，这种模式更类似于未受干扰的小鼠。在这里，我们将检查这种恢复的 Fos 模式与特定 SCN 输入途径标记物的关系，这些标记物已知与运动诱导的夹带、神经肽 Y (NPY) 和血清素 (5HT) 相关。我们还将使用 RNA-seq 检查这种调节背后的分子介质，以确定这些途径的受体是否上调。