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

通过信号处理了解环境破坏对生物计时系统的影响。

• 批准号: 9386306
• 负责人: Benjamin Lee Smarr
• 金额: $ 9.87万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386306
• 关键词: Address; Adrenal Glands; Affect; Animals; Automobile Driving; Back; Behavioral; Biological; Biological Models; Body Temperature; Body Temperature Changes; Brain; Cells; Cellular Phone; Chronic; Circadian Rhythms; Corticosterone; Coupling; Cues; Darkness; Data; Development; Diabetes Mellitus; Disease; Dose; Dysmenorrhea; Dyspepsia; Endocrine; Endocrine system; Environment; Environmental Impact; Estradiol; Feedback; Female; Frequencies; Future; Genetic; Glucocorticoids; Health; Hormonal; Hormonal Change; Hour; Human; Hypothalamic structure; Impaired cognition; Impairment; Implant; Individual; Infertility; Inflammation; Investigation; Jet Lag Syndrome; Life; Light; Lighting; Machine Learning; Malignant Neoplasms; Mammals; Measures; Mental Depression; Modeling; Modernization; Monitor; Myocardial Infarction; Obesity; Operative Surgical Procedures; Organ; Orphan; Output; Ovulation; Pattern; Periodicity; Persons; Pharmacology; Phase; Physiological; Physiology; Pituitary-Adrenal System; Planet Earth; Pollution; Prevention strategy; Preventive treatment; Rattus; Records; Regulation; Research Infrastructure; Resolution; Risk; Risk Marker; Sampling; Schools; Shapes; Signal Transduction; Social Obligations; Spermatogenesis; Stress; Stroke; Structure; System; Testing; Testosterone; The Sun; Time; Tissues; Wireless Technology; Work; base; biological systems; body system; comparative; drinking; feeding; high risk; male; mathematical model; minimally invasive; pituitary gonadal axis; predicting response; predictive modeling; rapid detection; reconstruction; resilience; response; shift work; signal processing; social; suprachiasmatic nucleus; targeted treatment; temporal measurement; time use

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.

项目概要/摘要。 地球上的生命进化到从太阳那里获得时间线索。因此，哺乳动物体内的大多数或所有细胞 利用遗传反馈回路来计算它们的每日（昼夜）节律。当一个人或任何哺乳动物看到光， 下丘脑视交叉上核（SCN）中的昼夜节律时钟。的scn 反过来又有助于保持无数其他组织和内分泌节律的同步，使健康。现代 环境对这种内部同步具有高度破坏性。夜晚的手机灯光或城市光污染， 而像学校上课时间或轮班制这样的社会强制性规定都是"时间污染"，造成损失 内部同步的。疾病越严重，患各种疾病的风险就越高， 包括肥胖症、癌症、不孕症、抑郁症以及最终的认知能力下降。如果不知道这些 系统通常保持同步，或者哪些系统通常是同步的，很难理解什么是同步的。 会降低健康。这个问题因为一些生物系统 除了昼夜节律周期外，还具有超昼夜（每隔几小时）和亚昼夜（每隔几天）周期。的 下丘脑-垂体-肾上腺轴（HPA）通过负反馈产生超昼夜节律，但也 下丘脑-垂体-性腺轴（HPG）显示出同样的负性， 反馈超日活动，昼夜节律，以及排卵和精子发生的亚日节律。 这两个轴由SCN调节。最近的研究表明，这些轴之间存在串扰， 他们的荷尔蒙分泌--皮质酮、雌二醇（女性）和睾酮（男性）， - 分别工作以同步额外SCN组织和进食和饮水的行为节律（FaD）。 最后，SCN、HPA和HPG轴都影响核心体温（CBT），使得高时间分辨率 CBT的记录包含关于这些系统跨时间尺度的循环和同步的信息。 该建议有三个目的，使用大鼠作为模型系统：1）在高时间分辨率下测试 HPA轴、HPG轴和SCN变化对CBT的影响。2)使用这些关系来构建一个模型， 可以根据以下的高时间分辨率CBT记录反向预测HPA轴、HPG轴和SCN的状态 一个特定的个体。3)将大鼠暴露于6小时"时差"相位提前形式的环境时间中断 的光周期，并使用该模型来预测这些系统在1分钟的时间响应 分辨率这项工作将采用手术和药理学前后的动物内比较 图10显示了对大鼠的操作，其FaD、活动和CBT以1分钟的分辨率连续捕获。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。所得 该模型将允许在真实的环境中对生理系统的环境破坏进行微创探索 时间该模型将被用来量化同步，因为它被破坏和重新出现，识别风险标志 或恢复力，并为未来的预防策略和治疗工作提出假设。