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，计时运动可以恢复失调的中央生物钟的节奏。尽管运动对整体健康的益处众所周知，但有限的研究利用运动作为恢复时钟功能的一种方式，特别是在SCN中。运动可以改变生物钟，引起昼夜节律的相移效应，但其机制尚不清楚。特别是，在这种运动引起的夹带周边时钟的SCN的协调努力还不完全清楚。最近有报道称，人类下午三点左右的运动可以使外周分子钟发生相移，但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SCN中。我们的实验室利用了一个发表得很好的昼夜节律紊乱的啮齿动物模型。此外，将我的运动科学专业知识与我们建立的昼夜节律破坏模型相结合，使我们的实验室有资格研究这一目标。该提案将实施光周期的中断，以模拟人类中所见的慢性昼夜节律中断。然后进行锻炼，以测试是否可以恢复正常的节奏。在这项试点研究中，我们建议测试我们的中心假设，即在昼夜节律中断期间运动将通过一个由两个实验组成的特定目标重新调整中断的中央昼夜节律钟。我们的目标是更好地了解运动如何在昼夜节律中断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，通过连续的明暗周期相移进行计时运动，导致Fos表达模式（神经元激活的标志物）与未运动的小鼠相比更接近未中断的小鼠。在这里，我们将研究这种恢复的Fos模式的特定SCN输入途径，已知与运动诱导的夹带，神经肽Y（NPY）和5-羟色胺（5 HT）的标记物的关系。我们还将使用RNA-seq检查这种调制背后的分子介质，以确定这些途径的受体是否上调。