Integration of sleep/wake network models across multiple temporal and spatial sca

跨多个时间和空间尺度的睡眠/唤醒网络模型的集成

• 批准号: 9050862
• 负责人: Andrew John Phillips
• 金额: $ 24.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050862
• 关键词: Adenosine A1 Receptor; Adult; Affect; Area; Arousal; Behavior; Behavioral; Biological Models; Biological Neural Networks; Biometry; Brain Stem; Cell Nucleus; Chronic; Circadian Rhythms; Data; Development; Development Plans; Disease; Educational process of instructing; Environment; Equation; Functional disorder; Goals; Grant; Guidelines; Head; Health; Heterogeneity; Homeostasis; Hospitals; Hour; Human; Hypothalamic structure; Inpatients; Lead; Leadership; Learning; Length; Link; Location; Mammals; Medicine; Mentors; Mentorship; Modeling; Narcolepsy; Neurons; Noise; Organism; Output; Pathology; Performance; Phenotype; Physiological; Physiology; Population; Process; Property; Protocols documentation; Publications; Purinergic P1 Receptors; Rattus; Research; Research Personnel; Rest; Schedule; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Statistical Distributions; Structure; System; Testing; Theoretical model; Time; Training; Up-Regulation; Woman; Work; age effect; base; career; career development; circadian pacemaker; computational neuroscience; experience; human data; improved; in vivo; innovation; mathematical model; medical schools; millisecond; models and simulation; network models; predictive modeling; receptor; receptor density; relating to nervous system; research and development; research study; response; skills; suprachiasmatic nucleus; theories; therapy design; voltage

Summary Sleep in mammals is regulated on multiple temporal and spatial scales. Recent experimental findings have revealed the importance of neuronal sleep/wake control systems in the brainstem and hypothalamus operating on the millisecond timescale that affect the organism's behavior on the hour timescale. These systems include mutually inhibitory sleep-promoting and wake-promoting nuclei that together comprise the “sleep/wake switch”. It has been proposed that inputs to this switch, including the output of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus, and the sleep homeostatic process produce the observed sleep/wake cycles. This sleep/wake switch theory has become the basis for understanding some sleep disorders (e.g., narcolepsy) and the effects of aging on sleep. In the last 6 years, several mathematical models of this system have been proposed at different spatial scales, including neural mass (neuronal population level) and neuronal network (single neuron level) models. These models have been used for relating behavioral phenotypes to underlying physiology and testing assumptions about our theoretical models of sleep. However, the existing models are limited in their spatial and temporal scales, making it impossible to study multi-scale interactions, e.g., interactions between chronic sleep restriction (long timescale) and sleep fragmentation (short timescale). Moreover, model assumptions about the spatial and temporal properties of the underlying physiology have not been tested. Mathematical models have proven important in defining normal and abnormal physiological relationships, and testing potential treatments in many health- related areas. Therefore, integrating models of sleep across spatial and temporal scales will improve understanding of sleep physiology and pathophysiology, and be instrumental in designing interventions. To achieve integration of sleep models across spatial and temporal scales, we will pursue four linked goals. (i) To determine the conditions under which neural mass models and neuronal network models of the sleep/wake switch predict the same dynamics. We will develop a neuronal network version of our existing neural mass model and test the effects of parameter heterogeneity, network size, and network connectivity. (ii) To test the hypothesis that sleep is inherently fragmented on short timescales due to noisy input to the sleep/wake switch. To achieve this, we will incorporate noisy inputs into both neural mass and neuronal network models and compare predictions to human data from an inpatient protocol. (iii) To test the hypothesis that chronic sleep restriction effects on sleep and performance are due to an interaction between the sleep/wake switch and long timescale dynamics of adenosine receptors. To achieve this, we will add long timescale dynamics of adenosine receptor density to both of our models; up-regulation of A1 receptors has been proposed to underlie the observed sleep and performance responses to chronic sleep restriction. Model predictions will be compared to human data from a chronic sleep restriction protocol. (iv) Sleep/wake switch models predict that the stability of sleep and wake states should decrease as a sleep/wake transition approaches. Consequently, variability in firing rates and voltages of neurons in the sleep/wake switch should increase prior to a transition. We will test this prediction by comparing the predictions of both models to in vivo multi-unit recordings of the sleep/wake switch nuclei in freely behaving rats. Our work will: (i) Develop a standardized approach to modeling sleep physiology. (ii) Lead to the development of predictive models of sleep that are applicable to a wider range of domains, including sleep fragmentation and chronic sleep restriction. (iii) Provide the first direct quantitative test of the sleep/wake switch theory. These important goals are related but can also be achieved independently. Dr. Phillips' strong background in mathematical modeling of sleep and circadian rhythms provides him with the ideal expertise to tackle this project. He will also be greatly assisted by the experimental and mathematical expertise of his mentor, Dr. Klerman, who is head of the Analytic & Modeling Unit within the Division of Sleep Medicine (DSM) at Brigham & Women's Hospital, Harvard Medical School (HMS). The rich research environment at HMS provides extremely fertile ground for interdisciplinary and collaborative projects. In parallel with these research plans, we have prepared a detailed personal development plan to enable Dr. Phillips to build new skills and transition smoothly to independence. Dr. Phillips' immediate goals are to (i) expand his skills in computational neuroscience; (ii) receive focused training in biostatistics; (iii) build his experience in teaching, mentorship, leadership, and organization; and (iv) produce high impact publications in the fields of sleep and circadian research. His plan to receive focused training in areas (i), (ii), and (iii) is described in the proposal. The proposed research plan should also lead to high impact publications, due to its innovative approach, timeliness, and importance. This research and career development plan will build upon Dr. Phillips' existing research and expertise, and will open many new research directions for his career as an independent researcher. The proposed project will grant Dr. Phillips the necessary protected time to conduct research, achieve the necessary experience, and learn the requisite skills to achieve these long-term goals.

概括 最近的实验结果表明，哺乳动物的睡眠在多个时间和空间尺度上受到调节。 揭示了神经睡眠/觉醒控制系统在脑干和下丘脑运作中的重要性 在毫秒时间尺度上影响有机体在小时时间尺度上的行为这些系统包括。 相互抑制的促进睡眠和促进唤醒的核，共同构成“睡眠/觉醒开关”。 有人建议该开关的输入，包括位于主昼夜节律起搏器的输出 哺乳动物下丘脑的视交叉上核 (SCN) 和睡眠稳态过程 产生观察到的睡眠/觉醒周期。这种睡眠/觉醒转换理论已成为以下理论的基础： 了解一些睡眠障碍（例如发作性睡病）以及衰老对睡眠的影响 在过去 6 年中， 已经在不同的空间尺度上提出了该系统的几个数学模型，包括神经网络 质量（神经元群体水平）和神经网络（单个神经元水平）模型已经成为这些模型。 用于将行为表型与基础生理学联系起来并测试关于我们理论的假设 然而，现有的睡眠模型在空间和时间尺度上受到限制。 不可能研究多尺度相互作用，例如慢性睡眠限制（长时间尺度）之间的相互作用 和睡眠碎片（短时间尺度）此外，关于空间和时间的模型假设。 基础生理学的特性尚未被证明很重要。 定义正常和异常的生理关系，并测试许多健康方面的潜在治疗方法 因此，跨空间和时间尺度的睡眠模型的整合将会得到改善。 了解睡眠生理学和病理生理学，并有助于设计干预措施。 为了实现跨空间和时间尺度的睡眠模型的整合，我们将追求四个相互关联的目标。 (i) 确定神经质量模型和神经网络模型的条件 我们将开发现有的神经网络版本。 神经质量模型并测试参数异质性、网络大小和网络连接性的影响。 (ii) 检验这样的假设：由于睡眠的噪声输入，睡眠本质上在短时间尺度上是碎片化的。 为了实现这一点，我们将把噪声输入纳入神经质量和神经元中。 网络模型并将预测与住院协议中的人类数据进行比较。 (iii) 检验以下假设：长期睡眠限制对睡眠和表现的影响是由于 睡眠/觉醒开关与腺苷受体的长时间尺度动态之间的相互作用来实现。 为此，我们将在我们的两个模型中添加腺苷受体密度的长期动态变化； A1 受体被认为是观察到的睡眠和对长期睡眠的表现反应的基础 模型预测将与长期睡眠限制方案的人类数据进行比较。 (iv) 睡眠/唤醒切换模型预测睡眠和唤醒状态的稳定性会随着时间的推移而降低 检查睡眠/觉醒转换方法，神经元的放电率和电压的变化。 睡眠/唤醒开关应该在转换之前增加我们将通过比较预测来测试这个预测。 两种模型对自由行为大鼠的睡眠/觉醒开关核的体内多单元记录。 我们的工作将：（i）开发一种标准化的睡眠生理学建模方法。 开发适用于更广泛领域的睡眠预测模型，包括睡眠 (iii) 首次提供睡眠/唤醒开关的直接定量测试 这些重要目标是相关的，但也可以独立实现。 菲利普斯博士在睡眠和昼夜节律数学建模方面的深厚背景为他提供了 解决这个项目的理想专业知识也将得到实验和数学的极大帮助。 他的导师 Klerman 博士是睡眠部门分析和建模部门的负责人，他的专业知识 布莱根妇女医院 (DSM)、哈佛医学院 (HMS) 的医学 (DSM) 丰富的研究。 HMS 的环境为跨学科和协作项目提供了极其肥沃的土壤。 在这些研究计划的同时，我们还准备了详细的个人发展计划，以使博士能够成为可能。 菲利普斯博士的近期目标是（i）培养新技能并顺利过渡。 扩展他在计算神经科学方面的技能；(ii) 接受生物统计学方面的集中培训； 教学、指导、领导和组织方面的经验；(iv) 在以下领域发表高影响力的出版物； 他计划在 (i)、(ii) 和 (iii) 领域接受重点培训。 由于其提案中所描述的，拟议的研究计划也应该会产生高影响力的出版物。 该研究和职业发展计划将建立在创新方法、及时性和重要性的基础上。 菲利普斯博士现有的研究和专业知识，将为他的职业生涯开辟许多新的研究方向 拟议的项目将为菲利普斯博士提供必要的受保护时间来进行研究。 研究、获得必要的经验并学习实现这些长期目标所需的技能。