Understanding the impact of environmental disruption in biological timing systems through signal processing.

项目摘要/摘要。 地球上的生命进化到接受太阳的时间提示。因此，哺乳动物体内的大部分或所有细胞 使用遗传反馈环来计时它们的日常(昼夜)节律。当人类或任何哺乳动物看到光时， 这在下丘脑视交叉上核(SCN)上为一个精心安排的昼夜节律的大脑时钟上发条。南华早报 反过来，有助于保持无数其他组织和内分泌节律的同步，使健康成为可能。现代的 环境对这种内部同步性具有很强的破坏性。晚上手机发出的光或城市的光污染， 而像学校开学时间或轮班这样的社会强加都会造成损失，这就是“时间污染” 内在的同步性。不同步化越严重，患各种疾病的风险就越高， 包括肥胖、癌症、不孕不育、抑郁以及最终的认知能力下降。在不知道这些是如何 系统通常保持同步或哪些系统正常同步，很难理解是什么 在去同步化中发生，从而降低健康水平。这个问题变得复杂起来，因为一些生物系统 除了昼夜节律外，还有超长周期(每隔几个小时)和亚周期(每隔几天)。这个 下丘脑-垂体-肾上腺轴(HPA)通过负反馈产生超常节律，但也 显示出强烈的昼夜节律；下丘脑-垂体-性腺轴(HPG)也显示出同样的负值 反馈超常活动，昼夜节律，以及排卵和精子发生的亚周期节律。 这两个轴由SCN调节。最近的研究表明，这些轴之间存在串扰， 他们的荷尔蒙输出--皮质酮、雌二醇(女性)和睾酮(男性)， 分别-努力使SCN以外的组织与进食和饮水的行为节律(FAD)同步。 最后，SCN、HPA和HPG轴都会影响核心体温(CBT)，因此高时间分辨率 CBT的记录包含有关这些系统跨时间尺度的循环和同步的信息。 该方案有三个目的，以大鼠为模型系统：1)在高时间分辨率下测试 HPA轴、HPG轴和SCN改变对CBT的影响。2)使用这些关系构建一个模型， 可以从高时间分辨率的CBT记录中反向预测HPA轴、HPG轴和SCN的状态 一个特定的个体。3)以6小时“时差”提前的形式使大鼠暴露在环境的时间中断中 并使用该模型来预测这些系统在1分钟的时间内的响应 决议。这项工作将采用手术和药物治疗前后的动物内比较。 以1分钟的分辨率连续捕捉FAD、活动和CBT的大鼠的操作。这些数据 将使用信号处理和机器学习进行分析，以定义模式和关系。由此产生的 模型将允许对跨生理系统的环境破坏进行微创探索 时间到了。该模型将被用来量化同步性，当它被中断并重新出现时，识别风险的标记 或复原力，并为预防战略和治疗的未来工作产生假设。

Project Summary/Abstract. Life on Earth evolved to take time cues from the Sun. Consequently, most or all cells in the mammalian body use genetic feedback loops to time their daily (circadian) rhythms. When a person or any mammal sees light, that winds an orchestrating circadian brain clock in the hypothalamic suprachiasmatic nucleus (SCN). The SCN in turn helps keep the myriad other tissue and endocrine rhythms in synchrony, enabling health. The modern environment is highly disruptive to this internal synchrony. Light at night from cell phones or urban light pollution, and social impositions like school start times or rotating work shifts all act as “temporal pollution,” causing loss of internal synchrony. The more severe the desynchrony, the higher the risk for a broad range of diseases, including obesity, cancer, infertility, depression and ultimately cognitive decline. Without knowing how these systems normally maintain synchrony or which systems are normally synchronized, it is hard to understand what happens in desynchrony to degrade health. This problem is complicated by the fact that some biological systems have ultradian (every few hours) and infradian (every few days) cycles in addition to circadian cycles. The hypothalamo-pituitary-adrenal axis (HPA) generates ultradian rhythms through negative feedback, but also shows a strong circadian cycle; the hypothalamo-pituitary-gonadal axis (HPG) shows the same negative feedback ultradian activity, circadian rhythmicity, and also infradian rhythms of ovulation and spermatogenesis. These two axes are regulated by the SCN. Recent work indicates that there is cross-talk between these axes, and that their hormonal outputs - corticosterone, and estradiol (in females) and testosterone (in males), respectively – work to synchronize extra-SCN tissues and behavioral rhythms of feeding and drinking (FaD). Finally, the SCN, HPA, and HPG axes all affect core body temperature (CBT), so that high temporal resolution recordings of CBT contain information about the cycling and synchrony of these systems across time scales. There are three aims to this proposal, using rats as a model system: 1) Test at high temporal resolution the effects of changes to the HPA axis, HPG axis, and SCN on CBT. 2) Use these relationships to build a model that can back-predict the state of the HPA axis, HPG axis, and SCN from a high temporal resolution CBT record of a given individual. 3) Expose rats to environmental temporal disruption in the form of a 6 h “jetlag” phase advance of the light cycle, and use the model to predict the response across these systems at 1-minute temporal resolution. This work will employ within-animal comparisons before and after surgical and pharmacological manipulations of rats whose FaD, activity, and CBT are captured continuously at 1-minute resolution. These data will be analyzed using signal-processing and machine learning to define patterns and relationships. The resulting model will allow minimally-invasive exploration of environmental disruption across physiological systems in real time. The model will be used to quantify synchrony as it is disrupted and re-emerges, identifying markers for risk or resilience, and generating hypotheses for future work into preventive strategies and treatments.