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.

项目摘要/摘要。 地球上的生命进化为从太阳中汲取时间提示。因此，哺乳动物体内的大多数或所有细胞 使用遗传反馈循环为他们的日常（昼夜节律）节奏计时。当一个人或任何哺乳动物看到光时， 这会在下丘脑上的核（SCN）中缠绕昼夜节律脑时钟。 SCN 反过来，有助于保持无数其他组织和内分泌节奏，使其能够健康。现代 环境对这种内部同步高度破坏。夜间从手机或城市光污染中照明， 诸如学校起步时间或旋转工作之类的社会征收都会改变所有的“时间污染”，从而造成损失 内部同步。越来越严重的是，多种疾病的风险越高， 包括肥胖，癌症，不育，抑郁症以及最终认知能力下降。不知道这些 系统通常保持同步或通常同步的系统，很难理解什么 发生在降解健康状况的降解中。某些生物系统的事实使这个问题变得复杂 除昼夜节律外，有超级（每隔几个小时）和基础（每隔几天）周期。这 下丘脑 - 垂体 - 肾上腺轴（HPA）通过负反馈产生超级节奏，但也会产生 显示出强烈的昼夜节律；下丘脑 - 垂体 - 基达轴（HPG）显示出相同的负 反馈超级活动，昼夜节律以及排卵和精子发生的基础节奏。 这两个轴由SCN调节。最近的工作表明这些轴之间存在串扰， 并且他们的马式输出 - 皮质酮和雌二醇（女性）和睾丸激素（男性）， 分别 - 努力同步额外的SCN组织和喂养和饮酒的行为节奏（FAD）。 最后，SCN，HPA和HPG轴都会影响核心体温（CBT），因此高临时分辨率 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。 该提案有三个目标，使用大鼠作为模型系统：1）高临时分辨率测试 HPA轴，HPG轴和SCN对CBT的变化的影响。 2）使用这些关系来建立一个模型 可以从高临时分辨率CBT记录中进行后预测HPA轴，HPG轴和SCN的状态 给定的个人。 3）将大鼠暴露于6小时“喷气仪”阶段的形式的环境暂时破坏 光周期的光周期，并使用该模型在1分钟的临时性下预测这些系统之间的响应 解决。这项工作将在手术和药理之前和之后进行动物内比较 以1分钟的分辨率连续捕获其FAD，活性和CBT的大鼠操纵。这些数据 将使用信号处理和机器学习来分析以定义模式和关系。结果 模型将允许实际侵入性探索真实物理系统的环境破坏 时间。该模型将用于量化同步，因为它是残疾人的并重新出口，识别风险标记 或韧性，并为未来的工作产生假设，以进行预防策略和治疗。